The Concise Guide to PHARMACOLOGY 2013/14: ion channels.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Ion channels are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An Introduction to Ion Channels

Overview: Ion channels are pore-forming proteins that allow the flow of ions across membranes, either plasma membranes or the membranes of intracellular organelles (Hille, 2001). Many ion channels (such as most Na, K Ca and some Cl channels) are gated by voltage but others (such as certain K and Cl channels, TRP channels, ryanodine receptors and IP3 receptors) are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators. As such, there is some blurring of the boundaries between “ion channels” and “ligand-gated channels” which are compiled separately in the Concise Guide to PHARMACOLOGY 2013/14.

Resolution of ion channel structures, beginning with K channels (Doyle et al., 1998) then Cl channels (Dutzler et al., 2002) and most recently Na channels (Payandeh et al., 2011) has greatly improved understanding of the structural basis behind ion channel function. Many ion channels (e.g., K, Na, Ca, HCN and TRP channels) share several structural similarities. These channels are thought to have evolved from a common ancestor and have been classified together as the “voltage-gated-like (VGL) ion channel chanome” (see Yu et al., 2005). Other ion channels, however, such as Cl channels, aquaporins and connexins, have completely different structural properties to the VGL channels, having evolved quite separately.

Currently, ion channels (including ligand-gated ion channels) represent the second largest target for existing drugs after G protein-coupled receptors (Overington et al., 2006). However, the advent of novel, faster screening techniques for compounds acting on ion channels (Dunlop et al., 2008) suggests that these proteins represent promising targets for the development of additional, novel therapeutic agents in the near future.

Nomenclature	ASIC1	ASIC2	ASIC3
HGNC, UniProt	ASIC1, P78348	ASIC2, Q16515	ASIC3, Q9UHC3
Endogenous activators (EC50)	Extracellular H+ (ASIC1a) (∼1.6x10-7 – 6.3x10-7 M), Extracellular H+ (ASIC1b) (∼6.3x10-7 – 8x10-6 M)	Extracellular H+ (∼1x10-5 – 8x10-5 M)	Extracellular H+ (transient component) (∼2x10-7 – 6.3x10-7 M), Extracellular H+ (sustained component) (∼5x10-5 – 3.5x10-4 M)
Activators (EC50)	–	–	GMQ (largely non-desensitizing; at pH 7.4) (∼1x10-3 M), arcaine (at pH 7.4) (∼1.2x10-3 M), agmatine (at pH 7.4) (∼9.8x10-3 M)
Channel Blockers (IC50)	psalmotoxin 1 (ASIC1a) (9x10-10 M), Zn2+ (ASIC1a) (∼7x10-9 M), Pb2+ (ASIC1b) (∼1.5x10-6 M), A317567 (ASIC1a) (∼2x10-6 M), Pb2+ (ASIC1a) (∼4x10-6 M), amiloride (ASIC1a) (1x10-5 M), benzamil (ASIC1a) (1x10-5 M), EIPA (ASIC1a) (1x10-5 M), nafamostat (ASIC1a) (∼1.3x10-5 M), amiloride (ASIC1b) (2.1x10-5 – 2.3x10-5 M), flurbiprofen (ASIC1a) (3.5x10-4 M), ibuprofen (ASIC1a) (∼3.5x10-4 M), Ni2+ (ASIC1a) (∼6x10-4 M)	amiloride (2.8x10-5 M), A317567 (∼3x10-5 M), nafamostat (∼7x10-5 M), Cd2+ (∼1x10-3 M)	APETx2 (transient component only) (6.3x10-8 M), nafamostat (transient component) (∼2.5x10-6 M), A317567 (∼1x10-5 M), amiloride (transient component only - sustained component enhanced by 200μM amiloride at pH 4) (1.6x10-5 – 6.3x10-5 M), Gd3+ (4x10-5 M), Zn2+ (6.1x10-5 M), aspirin (sustained component) (9.2x10-5 M), diclofenac (sustained component) (9.2x10-5 M), salicylic acid (sustained component) (2.6x10-4 M)
Radioligands (Kd)	[125I]psalmotoxin 1 (ASIC1a) (2.13x10-10 M)	–	–
Functional characteristics	ASIC1a: γ ∼14pS, PNa/PK = 5–13, PNa/PCa =2.5, rapid activation rate (5.8–13.7 ms), rapid inactivation rate (1.2–4 s) @ pH 6.0, slow recovery (5.3–13s) @ pH 7.4 ASIC1b: γ ∼ 19 pS, PNa/PK =14.0, PNa ≫ PCa, rapid activation rate (9.9 ms), rapid inactivation rate (0.9–1.7 s) @ pH 6.0, slow recovery (4.4–7.7 s) @ pH 7.4	γ∼10.4–13.4 pS, PNa/PK =10, PNa/PCa = 20, rapid activation rate, moderate inactivation rate (3.3–5.5 s) @ pH 5	γ∼ 13–15 pS; biphasic response consisting of rapidly inactivating transient and sustained components; very rapid activation (<5 ms) and inactivation (0.4s); fast recovery (0.4–0.6 s) @ pH 7.4, transient component partially inactivated at pH 7.2
Comment	ASIC1a and ASIC1b are also blocked by diarylamidines (IC50 ∼3 μM for ASIC1a)	ASIC2 is also blocked by diarylamidines	ASIC3 is also blocked by diarylamidines

Nomenclature	AQP0	AQP1	AQP2	AQP3	AQP4	AQP5	AQP6	AQP7	AQP8	AQP9	AQP10
HGNC, UniProt	MIP, P30301	AQP1, P29972	AQP2, P41181	AQP3, Q92482	AQP4, P55087	AQP5, P55064	AQP6, Q13520	AQP7, O14520	AQP8, O94778	AQP9, O43315	AQP10, Q96PS8
Permeability	water (low)	water (high)	water (high)	water (high), glycerol	water (high)	water (high)	water (low), anions	water (high), glycerol	water (high)	water (low), glycerol	water (low), glycerol
Endogenous activators	–	cGMP	–	–	–	–	–	–	–	–	–
Inhibitors	Hg2+	Ag+, Hg2+, tetraethylammonium	Hg2+	Hg2+ (also inhibited by acid pH)	–	Hg2+	Hg2+	Hg2+	Hg2+	Hg2+, phloretin	Hg2+
Comment	–	–	–	AQP3 is also inhibited by acid pH	AQP4 is inhibited by PKC activation	–	AQP6 is an intracellular channel permeable to anions as well as water 55	–	–	–	–

Nomenclature	CatSper1	CatSper2	CatSper3	CatSper4
HGNC, UniProt	CATSPER1, Q8NEC5	CATSPER2, Q96P56	CATSPER3, Q86XQ3	CATSPER4, Q7RTX7
Activators	CatSper1 is constitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation. In human, but not mouse, spermatozoa progesterone (EC50 ∼ 8 nM) also potentiates the CatSper current (ICatSper).	–	–	–
Channel Blockers (IC50)	NNC55-0396 (2x10-6 – 1x10-5 M), ruthenium red (1x10-5 M), HC056456 (2x10-5 M), mibefradil (3x10-5 M), Cd2+ (2x10-4 M), Ni2+ (3x10-4 M)	–	–	–
Functional characteristics	Calcium selective ion channel (Ba2+>Ca2+>>Mg2+>>Na+); quasilinear monovalent cation current in the absence of extracellular divalent cations; alkalinization shifts the voltage-dependence of activation towards negative potentials [V½ @ pH 6.0 = +87 mV (mouse); V½ @ pH 7.5 = +11mV (mouse) or pH 7.4 = +85 mV (human)]	Required for ICatSper	Required for ICatSper	Required for ICatSper

Nomenclature	ClC-1	ClC-2	ClC-Ka	ClC-Kb
HGNC, UniProt	CLCN1, P35523	CLCN2, P51788	CLCNKA, P51800	CLCNKB, P51801
Endogenous activators	–	arachidonic acid	–	–
Activators (EC50)	–	lubiprostone, omeprazole	niflumic acid (1x10-5 – 1x10-3 M)	niflumic acid (1x10-5 – 1x10-3 M)
Channel Blockers (IC50)	9-A-C, Cd2+, fenofibric acid, S-(-)CPB, S-(-)CPP, niflumic acid, Zn2+	Cd2+, DPC, NPPB, Zn2+, GaTx2 (Kd 1.5x10-11 M) [voltage dependent-100.0 mV]	3-phenyl-CPP, DIDS, niflumic acid (>1x10-3 M)	3-phenyl-CPP, DIDS
Functional characteristics	γ = 1–1.5 pS; voltage-activated (depolarization) (by fast gating of single protopores and a slower common gate allowing both pores to open simultaneously); inwardly rectifying; incomplete deactivation upon repolarization, ATP binding to cytoplasmic cystathionine β-synthetase related (CBS) domains inhibits ClC-1 (by closure of the common gate), depending on its redox status	γ = 2–3 pS; voltage-activated by membrane hyperpolarization by fast protopore and slow cooperative gating; channels only open negative to ECl resulting in steady-state inward rectification; voltage dependence modulated by permeant anions; activated by cell swelling, PKA, and weak extracellular acidosis; potentiated by SGK1; inhibited by phosphorylation by p34(cdc2)/cyclin B; cell surface expression and activity increased by association with Hsp90	γ = 26 pS; linear current-voltage relationship except at very negative potentials; no time dependence; inhibited by extracellular protons (pK = 7.1); potentiated by extracellular Ca2+	Bidirectional rectification; no time dependence; inhibited by extracellular protons; potentiated by extracellular Ca2+
Comment	CIC-1 is constitutively active	CIC-2 is also activated by amidation	CIC-Ka is constitutively active (when co-expressed with barttin), and can be blocked by benzofuran derivatives	CIC-Kb is constitutively active (when co-expressed with barttin), and can be blocked by benzofuran derivatives

Nomenclature	ClC-3	ClC-4	ClC-5	ClC-6	ClC-7
HGNC, UniProt	CLCN3, P51790	CLCN4, P51793	CLCN5, P51795	CLCN6, P51797	CLCN7, P51798
Channel Blockers (IC50)	phloretin (3x10-5 M)	Zn2+ (5x10-5 M) 131, Cd2+ (6.8x10-5 M) 131	–	DIDS (1x10-3 M)	DIDS (4x10-5 M) 149, NS5818 (5.2x10-5 M) 149, NPPB (1.56x10-4 M) 149
Functional characteristics	Cl-/H+ antiporter 121; pronounced outward rectification; slow activation, fast deactivation; activity enhanced by CaM kinase II; inhibited by intracellular Ins(3,4,5,6)P4 and extracellular acidosis	Cl-/H+ antiporter (2Cl-:1H+) 79,134,146; extreme outward rectification; voltage-dependent gating with midpoint of activation at +73 mV 130; rapid activation and deactivation; inhibited by extracellular acidosis; non-hydrolytic nucleotide binding required for full activity	Cl-/H+ antiporter (2Cl-:1H+) 134,146,151,159; extreme outward rectification; voltage-dependent gating with midpoint of activation of 116.0 mV; rapid activation and deactivation; potentiated and inhibited by intracellular and extracellular acidosis, respectively; ATP binding to cytoplasmic cystathionine β-synthetase related (CBS) domains activates ClC-5	Cl-/H+ antiporter (2Cl-:1H+) 125; outward rectification, rapid activation and deactivation	Cl-/H+ antiporter (2Cl-:1H+) 103,114,149; strong outward rectification; voltage-dependent gating with a threshold more positive than ∼ + 20 mV; very slow activation and deactivation
Comment	insensitive to the channel blockers DIDS, NPPB and tamoxifen (10 μM)	–	insensitive to the channel blockers DIDS (1 mM), DPC (1 mM), 9-A-C (2 mM), NPPB (0.5 mM) and niflumic acid (1 mM)	–	active when co-expressed with Ostm1

Nomenclature	HGNC, UniProt	Activators (EC50)	Channel Blockers (IC50)	Functional characteristics	Comment
CFTR	CFTR, P13569	apigenin (Potentiation), capsaicin (Potentiation), CBIQ (Potentiation), felodipine (Potentiation), genistein (Potentiation), nimodipine (Potentiation), NS004 (Potentiation), phenylglycine-01 (Potentiation), SF-01 (Potentiation), UCCF-029 (Potentiation), UCCF-339 (Potentiation), UCCF-853 (Potentiation), VX-770 (Potentiation)	intracellular CFTRinh-172 (intracellular application prolongs mean closed time), GaTx1, glibenclamide, extracellular GlyH-101	γ = 6–10 pS; permeability sequence = Br- ≥ Cl- > I- > F-, (PI/PCl = 0.1–0.85); slight outward rectification; phosphorylation necessary for activation by ATP binding at binding nucleotide binding domains (NBD)1 and 2; positively regulated by PKC and PKGII (tissue specific); regulated by several interacting proteins including syntaxin 1A, Munc18 and PDZ domain proteins such as NHERF (EBP50) and CAP70	UCCF-339, UCCF-029, apigenin and genistein are examples of flavones. UCCF-853 and NS004 are examples of benzimidazolones. CBIQ is an example of a benzoquinoline. felodipine and nimodipine are examples of 1,4-dihydropyridines. phenylglycine-01 is an example of a phenylglycine. SF-01 is an example of a sulfonamide. Malonic acid hydrazide conjugates are also CFTR channel blockers (see Verkman and Galietta, 135 155)

Nomenclature	HGNC, UniProt	Endogenous activators (EC50)	Endogenous channel blockers (IC50)	Channel Blockers (IC50)	Functional characteristics
CaCC	ANO1, Q5XXA6	intracellular Ca2+	Ins(3,4,5,6)P4	9-A-C, DCDPC, DIDS, flufenamic acid, fluoxetine, mibefradil, niflumic acid, NPPB, SITS, tannic acid	γ = 0.5–5 pS; permeability sequence, SCN- > NO3-> I- > Br- > Cl- > F-; relative permeability of SCN-:Cl- ∼8. I-:Cl- ∼3, aspartate:Cl- ∼0.15, outward rectification (decreased by increasing [Ca2+]i); sensitivity to activation by [Ca2+]i decreased at hyperpolarized potentials; slow activation at positive potentials (accelerated by increasing [Ca2+]i); rapid deactivation at negative potentials, deactivation kinetics modulated by anions binding to an external site; modulated by redox status

Nomenclature	Activators (EC50)	Endogenous channel blockers (IC50)	Channel Blockers (IC50)	Functional characteristics	Comment
Maxi Cl-	extracellular chlorpromazine, cytosolic GTPγS, extracellular tamoxifen, extracellular toremifene, extracellular triflupromazine	intracellular arachidonic acid	DPC, extracellular Gd3+, SITS, DIDS (4x10-5 M) 149, extracellular Zn2+ (5x10-5 M) 131, NPPB (1.56x10-4 M) 149	γ = 280–430 pS (main state); permeability sequence, I > Br > Cl > F > gluconate (PCIPCl = ∼1.5); ATP is a voltage dependent permeant blocker of single channel activity (PATP/PCl = 0.08–0.1); channel activity increased by patch-excision; channel opening probability (at steady-state) maximal within approximately ± 20 mV of 0 mV, opening probability decreased at more negative and (commonly) positive potentials yielding a bell-shaped curve; channel conductance and opening probability regulated by annexin 6	Maxi Cl- is also activated by G protein-coupled receptors and cell swelling. tamoxifen and toremifene are examples of triphenylethylene anti-oestrogens

Nomenclature	Activators (EC50)	Endogenous channel blockers (IC50)	Channel Blockers (IC50)	Functional characteristics	Comment
VRAC	GTPγS	arachidonic acid, extracellular Mg2+	1,9-dideoxyforskolin, 9-A-C, carbenoxolone, clomiphene, DCPIB, diBA-(5)-C4, DIDS, gossypol, IAA-94, mefloquine, mibefradil, nafoxidine, NDGA, NPPB, NS3728, quinidine, quinine, tamoxifen	γ = 10–20 pS (negative potentials), 50–90 pS (positive potentials); permeability sequence SCN > I > NO3- >Br- > Cl- > F- > gluconate; outward rectification due to voltage dependence of γ; inactivates at positive potentials in many, but not all, cell types; time dependent inactivation at positive potentials; intracellular ionic strength modulates sensitivity to cell swelling and rate of channel activation; rate of swelling-induced activation is modulated by intracellular ATP concentration; ATP dependence is independent of hydrolysis and modulated by rate of cell swelling; inhibited by increased intracellular free Mg2+ concentration; swelling induced activation of several intracellular signalling cascades may be permissive of, but not essential to, the activation of VRAC including: the Rho-Rho kinase-MLCK; Ras-Raf-MEK-ERK; PIK3-NOX-H2O2 and Src-PLCγ-Ca2+ pathways; regulation by PKCα required for optimal activity; cholesterol depletion enhances activity; activated by direct stretch of β1-integrin	VRAC is also activated by cell swelling and low intracellular ionic strength. VRAC is also blocked by chromones, extracellular nucleotides and nucleoside analogues

Nomenclature	Cx23, Cx25, Cx26, Cx30, Cx30.2, Cx30.3, Cx31, Cx31.1, Cx31.9, Cx32, Cx36, Cx37, Cx40, Cx40.1, Cx43, Cx45, Cx46, Cx47, Cx50, Cx59, Cx62	Px1, Px2, Px3
HGNC, UniProt	GJE1, A6NN92; GJB7, Q6PEY0; GJB2, P29033; GJB6, O95452; GJC3, Q8NFK1; GJB4, Q9NTQ9; GJB3, O75712; GJB5, O95377; GJD3, Q8N144; GJB1, P08034; GJD2, Q9UKL4; GJA4, P35212; GJA5, P36382; GJD4, Q96KN9; GJA1, P17302; GJC1, P36383; GJA3, Q9Y6H8; GJC2, Q5T442; GJA8, P48165; GJA9, P57773; GJA10, Q969M2	PANX1, Q96RD7; PANX2, Q96RD6; PANX3, Q96QZ0
Endogenous inhibitors	extracellular Ca2+ (blocked by raising external Ca2+)	–
Inhibitors	carbenoxolone, flufenamic acid, octanol	carbenoxolone, flufenamic acid (little block by flufenamic acid)
Comment	–	The pannexins are unaffected by raising external Ca2+

Nomenclature	CNGA1	CNGA2	CNGA3	CNGA4	CNGB1	CNGB3
HGNC, UniProt	CNGA1, P29973	CNGA2, Q16280	CNGA3, Q16281	CNGA4, Q8IV77	CNGB1, Q14028	CNGB3, Q9NQW8
Activators	cGMP (EC50 ∼ 30 μM) >> cAMP	cGMP ∼ cAMP (EC50 ∼ 1 μM)	cGMP (EC50 ∼ 30 μM) >> cAMP	–	–	–
Inhibitors	L-(cis)-diltiazem	–	L-(cis)-diltiazem	–	–	–
Functional characteristics	γ = 25–30 pS, PCa/PNa = 3.1	γ = 35 pS, PCa/PNa = 6.8	γ = 40 pS, PCa/PNa = 10.9	–	–	–

Nomenclature	HCN1	HCN2	HCN3	HCN4
HGNC, UniProt	HCN1, O60741	HCN2, Q9UL51	HCN3, Q9P1Z3	HCN4, Q9Y3Q4
Activators	cAMP > cGMP (both weak)	cAMP > cGMP	–	cAMP > cGMP
Inhibitors	Cs+, ivabradine, ZD7288	Cs+, ivabradine, ZD7288	Cs+, ivabradine, ZD7288	Cs+, ivabradine, ZD7288

Nomenclature	Subunits	Activators (EC50)	Channel Blockers (IC50)	Functional characteristics
ENaCαβγ	ENaC α, ENaC β, ENaC γ	S3969 (1.2x10-6 M) 200	P552-02 (7.6x10-9 M), benzamil (∼1x10-8 M), amiloride (1x10-7 – 2x10-7 M), triamterene (∼5x10-6 M) 189,196	γ ≈ 4–5 pS, PNa/PK > 20; tonically open at rest; expression and ion flux regulated by circulating aldosterone-mediated changes in gene transcription. The action of aldosterone, which occurs in ‘early’ (1.5–3 h) and ‘late’ (6–24 hr) phases is competitively antagonised by spironolactone, its active metabolites and eplerenone. Glucocorticoids are important functional regulators in lung/airways and this control is potentiated by thyroid hormone; but the mechanism underlying such potentiation is unclear 185,206,209. The density of channels in the apical membrane, and hence GNa, can be controlled via both serum and glucocorticoid-regulated kinases (SGK1, 2 and 3) 190,191 and via cAMP/PKA 203; and these protein kinases appear to act by inactivating Nedd-4/2, a ubiquitin ligase that normally targets the ENaC channel complex for internalization and degradation 186,190. ENaC is constitutively activated by soluble and membrane-bound serine proteases, such as furin, prostasin (CAP1), plasmin and elastase 197,198,204,207,208. The activation of ENaC by proteases is blocked by a protein, SPLUNC1, secreted by the airways and which binds specifically to ENaC to prevent its cleavage 192. Pharmacological inhibitors of proteases (e.g. camostat acting upon prostasin) reduce the activity of ENaC 202. Phosphatidylinositides such as PtIns(4,5)P2 and PtIns(3,4,5)P3) stabilise channel gating probably by binding to the β and γ ENaC subunits, respectively 201,205, whilst C terminal phosphorylation of β and γ-ENaC by ERK1/2 has been reported to inhibit the withdrawal of the channel complex from the apical membrane 212. This effect may contribute to the cAMP-mediated increase in sodium conductance.

Nomenclature	IP3R1	IP3R2	IP3R3
HGNC, UniProt	ITPR1, Q14643	ITPR2, Q14571	ITPR3, Q14573
Endogenous activators (EC50)	cytosolic ATP (< mM range), IP3 (endogenous; nM - μM range), cytosolic Ca2+ (Concentration range = < 7.5x10-4 M)	cytosolic Ca2+ (nM range), IP3 (endogenous; nM - μM range)	cytosolic Ca2+ (nM range), IP3 (endogenous; nM - μM range)
Activators (EC50)	adenophostin A (pharmacological; nM range), Ins(2,4,5)P3 (pharmacological; also activated by other InsP3 analogues)	adenophostin A (pharmacological; nM range), Ins(2,4,5)P3 (pharmacological; also activated by other InsP3 analogues)	–
Endogenous antagonists (IC50)	heparin (μg/ml)	heparin (μg/ml)	heparin (μg/ml)
Antagonists (IC50)	caffeine (mM range), decavanadate (μM range), PIP2 (μM range), xestospongin C (μM range)	decavanadate (μM range)	decavanadate (μM range)
Functional characteristics	Ca2+: (PBa/PK ∼6) single-channel conductance, ∼70 pS (50 mM Ca2+)	Ca2+: single-channel conductance, ∼70 pS (50 mM Ca2+), ∼390 pS (220 mM Cs+)	Ca2+: single-channel conductance, ∼88 pS (55 mM Ba2+)
Comment	IP3 R1 is also antagonised by calmodulin at high cytosolic Ca2+ concentrations	–	–

Nomenclature	Kir1.1	Kir2.1, Kir2.2, Kir2.3, Kir2.4	Kir3.1, Kir3.2, Kir3.3, Kir3.4	Kir4.1, Kir4.2	Kir5.1	Kir6.1, Kir6.2	Kir7.1
HGNC, UniProt	KCNJ1, P48048	KCNJ2, P63252; KCNJ12, Q14500; KCNJ4, P48050; KCNJ14, Q9UNX9	KCNJ3, P48549; KCNJ6, P48051; KCNJ9, Q92806; KCNJ5, P48544	KCNJ10, P78508; KCNJ15, Q99712	KCNJ16, Q9NPI9	KCNJ8, Q15842; KCNJ11, Q14654	KCNJ13, O60928
Endogenous inhibitors	–	intracellular Mg2+	–	–	–	–	–
Endogenous activators	–	–	PIP2	–	–	–	–
Associated subunits	–	–	–	–	–	SUR1, SUR2A, SUR2B	–
Activators	–	–	–	–	–	cromakalim, diazoxide, minoxidil, nicorandil	–
Inhibitors	–	–	–	–	–	glibenclamide, tolbutamide	–
Functional characteristics	Inward-rectifier current	IK1 in heart, ‘strong’ inward–rectifier current	G-protein-activated inward-rectifier current	Inward-rectifier current	Inward-rectifier current	ATP-sensitive, inward-rectifier current	Inward-rectifier current
Comment	–	KIR2.1 is also inhibited by intracellular polyamines, KIR2.2 is also inhibited by intracellular polyamines, KIR2.3 is also inhibited by intracellular polyamines, KIR2.4 is also inhibited by intracellular polyamines	KIR3.1 is also activated by Gβγ, KIR3.2 is also activated by Gβγ, KIR3.3 is also activated by Gβγ, KIR3.4 is also activated by Gβγ	–	–	–	–

Nomenclature	K2P1.1, K2P6.1, K2P7.1	K2P2.1, K2P10.1, K2P4.1	K2P3.1, K2P9.1, K2P15.1	K2P16.1, K2P5.1, K2P17.1	K2P13.1, K2P12.1	K2P18.1
HGNC, UniProt	KCNK1, O00180; KCNK6, Q9Y257; KCNK7, Q9Y2U2	KCNK2, O95069; KCNK10, P57789; KCNK4, Q9NYG8	KCNK3, O14649; KCNK9, Q9NPC2; KCNK15, Q9H427	KCNK16, Q96T55; KCNK5, O95279; KCNK17, Q96T54	KCNK13, Q9HB14; KCNK12, Q9HB15	KCNK18, Q7Z418
Endogenous activators (EC50)	–	arachidonic acid	–	–	–	–
Activators (EC50)	–	halothane, riluzole	halothane	–	–	–
Inhibitors	–	–	anandamide, ruthenium red	–	halothane	–
Endogenous inhibitors	–	–	–	–	–	arachidonic acid
Functional characteristics	Background current	Background current	Background current	Background current	Background current	Background current
Comment	K2P1.1 is inhibited by acid pHi, K2P6.1 is inhibited by acid pHi, K2P7.1 is inhibited by acid pHi	K2P2.1 is also activated by stretch, heat and acid pHi, K2P10.1 is also activated by stretch, heat and acid pHi, K2P4.1 is also activated by stretch, heat and acid pHi	K2P3.1 is also activated by alkakine pHo and inhibited by acid pHo, K2P9.1 is also inhibited by acid pHo, K2P15.1 is inhibited by acid pHo	K2P16.1 is activated by alkaline pHo, K2P5.1 is activated by alkaline pHo, K2P17.1 is activated by alkaline pHo	–	–

Nomenclature	Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, Kv1.7, Kv1.8	Kv2.1, Kv2.2	Kv3.1, Kv3.2, Kv3.3, Kv3.4	Kv4.1, Kv4.2, Kv4.3	Kv7.1, Kv7.2, Kv7.3, Kv7.4, Kv7.5	Kv10.1, Kv10.2, Kv11.1, Kv11.2, Kv11.3, Kv12.1, Kv12.2, Kv12.3	KCa1.1, KCa4.1, KCa4.2, KCa5.1	KCa2.1, KCa2.2, KCa2.3, KCa3.1
HGNC, UniProt	KCNA1, Q09470; KCNA2, P16389; KCNA3, P22001; KCNA4, P22459; KCNA5, P22460; KCNA6, P17658; KCNA7, Q96RP8; KCNA10, Q16322	KCNB1, Q14721; KCNB2, Q92953	KCNC1, P48547; KCNC2, Q96PR1; KCNC3, Q14003; KCNC4, Q03721	KCND1, Q9NSA2; KCND2, Q9NZV8; KCND3, Q9UK17	KCNQ1, P51787; KCNQ2, O43526; KCNQ3, O43525; KCNQ4, P56696; KCNQ5, Q9NR82	KCNH1, O95259; KCNH5, Q8NCM2; KCNH2, Q12809; KCNH6, Q9H252; KCNH7, Q9NS40; KCNH8, Q96L42; KCNH3, Q9ULD8; KCNH4, Q9UQ05	KCNMA1, Q12791; KCNT1, Q5JUK3; KCNT2, Q6UVM3; KCNU1, A8MYU2	KCNN1, Q92952; KCNN2, Q9H2S1; KCNN3, Q9UGI6; KCNN4, O15554
Associated subunits	Kv β1 and Kv β2	Kv5.1, Kv6.1–6.4, Kv8.1–8.2 and Kv9.1–9.3	MiRP2 is an associated subunit for Kv3.4	KChIP and KChAP	minK and MiRP2	minK and MiRP1	–	–
Activators (EC50)	–	–	–	–	retigabine	–	NS004, NS1619	–
Inhibitors	α-dendrotoxin, margatoxin, noxiustoxin, tetraethylammonium (potent)tetraethylammonium (moderate)4-aminopyridine (potent)	tetraethylammonium (moderate)	4-aminopyridine (potent), tetraethylammonium (potent)sea anemone toxin BDS-I	–	linopirdine, tetraethylammonium, XE991	astemizole, E4031, terfenadine	charybdotoxin, iberiotoxin, tetraethylammonium	apamin, charybdotoxin
Functional characteristics	KV, KA	KV	KV, KA	KA	cardiac IK5, M current, M current	cardiac IKR	Maxi KCa KNa (slack & slick)	SKCa, IKCa

Nomenclature	RyR1	RyR2	RyR3
HGNC, UniProt	RYR1, P21817	RYR2, Q92736	RYR3, Q15413
Endogenous activators (EC50)	cytosolic ATP (endogenous; mM range), luminal Ca2+ (endogenous), cytosolic Ca2+ (endogenous; μM range)	cytosolic ATP (endogenous; mM range), luminal Ca2+ (endogenous), cytosolic Ca2+ (endogenous; μM range)	cytosolic ATP (endogenous; mM range), cytosolic Ca2+ (endogenous; μM range)
Activators (EC50)	caffeine (pharmacological; mM range), ryanodine (pharmacological; nM - μM range), suramin (pharmacological; μM range)	caffeine (pharmacological; mM range), ryanodine (pharmacological; nM - μM range), suramin (pharmacological; μM range)	caffeine (pharmacological; mM range), ryanodine (pharmacological; nM - μM range)
Endogenous antagonists (IC50)	cytosolic Mg2+ (mM range), cytosolic Ca2+ (Concentration range = > 1x10-4 M)	cytosolic Mg2+ (mM range), cytosolic Ca2+ (Concentration range = > 1x10-3 M)	cytosolic Mg2+ (mM range), cytosolic Ca2+ (Concentration range = > 1x10-3 M)
Antagonists (IC50)	dantrolene	–	dantrolene
Channel Blockers (IC50)	procaine, ruthenium red, ryanodine (Concentration range = > 1x10-4 M)	procaine, ruthenium red, ryanodine (Concentration range = > 1x10-4 M)	ruthenium red
Functional characteristics	Ca2+: (P Ca/P K∼6) single-channel conductance: ∼90 pS (50mM Ca2+), 770 pS (200 mM K+)	Ca2+: (P Ca/P K∼6) single-channel conductance: ∼90 pS (50mM Ca2+), 720 pS (210 mM K+)	Ca2+: (P Ca/PK∼6) single-channel conductance: ∼140 pS (50mM Ca2+), 777 pS (250 mM K+)
Comment	RyR1 is also activated by depolarisation via DHP receptor, calmodulin at low cytosolic Ca2+ concentrations, CaM kinase and PKA; antagonised by calmodulin at high cytosolic Ca2+ concentrations	RyR2 is also activated by CaM kinase and PKA; antagonised by calmodulin at high cytosolic Ca2+ concentrations	RyR3 is also activated by calmodulin at low cytosolic Ca2+ concentrations; antagonised by calmodulin at high cytosolic Ca2+ concentrations

Nomenclature	HGNC, UniProt	Activators	Channel Blockers (IC50)	Functional characteristics
Navi2.1	NALCN, Q8IZF0	Constitutively active (Lu et al., 2007), or activated downstream of Src family tyrosine kinases (SFKs) (Lu et al., 2009; Swayne et al., 2009); positively modulated by decreased extracellular Ca2+ concentration (Lu et al., 2010) 222–224,226	Gd3+ (1.4x10-6 M), Cd2+ (1.5x10-4 M), Co2+ (2.6x10-4 M), verapamil (3.8x10-4 M)	γ = 27 pS (by fluctuation analysis), PNa/PCs = 1.3, PK/PCs = 1.2, PCa/PCs = 0.5, linear current voltage-relationship, voltage-independent and non-inactivating

Nomenclature	TRPC1	TRPC4	TRPC5
HGNC, UniProt	TRPC1, P48995	TRPC4, Q9UBN4	TRPC5, Q9UL62
Chemical activators	NO-mediated cysteine S-nitrosylation	–	–
Physical activators	membrane stretch (likely direct)	–	–
Other chemical activators	–	NO-mediated cysteine S-nitrosylation, potentiation by extracellular protons	NO-mediated cysteine S-nitrosylation (disputed), potentiation by extracellular protons
Physical activators	–	–	membrane stretch (likely indirect)
Endogenous activators (EC50)	–	–	lysophosphatidylcholine, intracellular Ca2+ (at negative potentials) (6.35x10-7 M)
Activators (EC50)	–	La3+ (μM range)	7,4'-dihydroxyisoflavone, genistein (independent of tyrosine kinase inhibition) 350, La3+ (μM range), Gd3+ (Concentration range = 1x10-4 M), Pb2+ (Concentration range = 5x10-6 M)
Channel Blockers (IC50)	2-APB, Gd3+, GsMTx-4, La3+, SKF96365	2-APB, La3+ (mM range), niflumic acid, SKF96365, ML204 (2.9x10-6 M) 299	2-APB, BTP2, chlorpromazine, flufenamic acid, GsMTx-4, KB-R7943, La3+ (mM range), SKF96365, ML204 (∼1x10-5 M) 299
Functional characteristics	γ = 16 pS (fluctuation analysis), conducts mono- and di-valent cations non-selectively; monovalent cation current suppressed by extracellular Ca2+; non-rectifying, or mildly inwardly rectifying; non-inactivating	γ = 30 –41 pS, conducts mono and di-valent cations non-selectively (PCa/PNa = 1.1 – 7.7); dual (inward and outward) rectification	γ = 41-63 pS; conducts mono-and di-valent cations non-selectively (PCa/PNa = 1.8 – 9.5); dual rectification (inward and outward) as a homomer, outwardly rectifying when expressed with TRPC1 or TRPC4

Nomenclature	TRPC3	TRPC6	TRPC7
HGNC, UniProt	TRPC3, Q13507	TRPC6, Q9Y210	TRPC7, Q9HCX4
Chemical activators	diacylglycerols	–	diacylglycerols
Other chemical activators	–	diacylglycerols	–
Physical activators	–	membrane stretch (likely indirect)	–
Endogenous activators (EC50)	–	20-HETE, arachidonic acid, lysophosphatidylcholine	–
Activators (EC50)	–	2,4 diahexanxoylphloroglucinol 287, flufenamate, hyperforin 288	–
Channel Blockers (IC50)	2-APB, ACAA, BTP2, Gd3+, KB-R7943, La3+, Ni2+, Pyr3 280, SKF96365	2-APB, ACAA, amiloride, Cd2+, Gd3+, GsMTx-4, Extracellular H+, KB-R7943, ML9, SKF96365, La3+ (∼6x10-6 M)	2-APB, amiloride, La3+, SKF96365
Functional characteristics	γ = 66 pS; conducts mono and di-valent cations non-selectively (PCa/PNa = 1.6); monovalent cation current suppressed by extracellular Ca2+; dual (inward and outward) rectification	γ = 28-37 pS; conducts mono and divalent cations with a preference for divalents (PCa/PNa = 4.5–5.0); monovalent cation current suppressed by extracellular Ca2+ and Mg2+, dual rectification (inward and outward), or inward rectification	γ = 25–75 pS; conducts mono and divalent cations with a preference for divalents (PCa/ PCs = 5.9); modest outward rectification (monovalent cation current recorded in the absence of extracellular divalents); monovalent cation current suppressed by extracellular Ca2+ and Mg2+

Nomenclature	TRPM1	TRPM3
HGNC, UniProt	TRPM1, Q7Z4N2	TRPM3, Q9HCF6
Physical activators	–	heat (Q10 = 7.2 between 15 - 25°C; Vriens et al., 2011), hypotonic cell swelling 346
Endogenous activators (EC50)	pregnenolone sulphate 285	epipregnanolone sulphate 294, pregnenolone sulphate 347
Activators (EC50)	–	dihydro-D-erythrosphingosine, nifedipine, sphingosine
Endogenous channel blockers (IC50)	Zn2+ (1x10-6 M)	intracellular Mg2+, extracellular Na+ (TRPM3α2 only)
Channel Blockers (IC50)	–	2-APB, Gd3+, La3+, mefenamic acid 281, pioglitazone (independent of PPAR-γ) 295, rosiglitazone, troglitazone
Functional characteristics	Conducts mono- and di-valent cations non-selectively, dual rectification (inward and outward)	TRPM31235: γ = 83 pS (Na+ current), 65 pS (Ca2+ current); conducts mono and di-valent cations non-selectively (PCa/PNa = 1.6) TRPM3α1: selective for monovalent cations (PCa/PCs∼0.1); TRPM3α2: conducts mono- and di-valent cations non-selectively (PCa/PCs = 1–10); Outwardly rectifying (magnitude varies between spice variants)

Nomenclature	HGNC, UniProt	Other chemical activators	Physical activators	Endogenous activators (EC50)	Activators (EC50)	Endogenous channel blockers (IC50)	Channel Blockers (IC50)	Functional characteristics
TRPM2	TRPM2, O94759	agents producing reactive oxygen (e.g. H2O2) and nitrogen (e.g. GEA 3162) species	heat ∼ 35°C	intracellular ADP ribose, arachidonic acid (Potentiation), intracellular cADPR, intracellular Ca2+ (via calmodulin), H2O2	GEA 3162	extracellular H+, Zn2+ (1x10-6 M)	2-APB, ACAA, clotrimazole, econazole, flufenamic acid, miconazole	γ = 52-60 pS at negative potentials, 76 pS at positive potentials; conducts mono- and di-valent cations non-selectively (PCa/PNa = 0.6–0.7); non-rectifying; inactivation at negative potentials; activated by oxidative stress probably via PARP-1, PARP inhibitors reduce activation by oxidative stress, activation inhibited by suppression of APDR formation by glycohydrolase inhibitors

Nomenclature	TRPM4	TRPM5
HGNC, UniProt	TRPM4, Q8TD43	TRPM5, Q9NZQ8
Other channel blockers	intracellular nucleotides including ATP, ADP, AMP and AMP-PNP with an IC50 range of 1.3–1.9 μM	–
Physical activators	membrane depolarization (V½ = -20 mV to + 60 mV dependent upon conditions) in the presence of elevated [Ca2+]i, heat (Q10 = 8.5 @ +25 mV between 15 and 25°C)	membrane depolarization (V½ = 0 to + 120 mV dependent upon conditions), heat (Q10 = 10.3 @ -75 mV between 15 and 25°C)
Endogenous activators (EC50)	intracellular Ca2+ (transient activation of whole cell current) (3x10-7 – 2x10-5 M)	intracellular Ca2+ (transient activation) (6.35x10-7 – 8.4x10-7 M)
Activators (EC50)	BTP2 (Potentiation), decavanadate	rosiglitazone 295
Channel Blockers (IC50)	9-phenanthrol, clotrimazole, flufenamic acid (2.8x10-6 M), intracellular spermine (3.5x10-5 – 6.1x10-5 M), adenosine (6.3x10-4 M)	flufenamic acid (2.4x10-5 M), intracellular spermine (3.7x10-5 M), Extracellular H+ (6.3x10-4 M)
Functional characteristics	γ = 23 pS (within the range 60 to +60 mV); permeable to monovalent cations; impermeable to Ca2+; strong outward rectification; slow activation at positive potentials, rapid deactivation at negative potentials, deactivation blocked by decavanadate	γ = 15-25 pS; conducts monovalent cations selectively (PCa/PNa = 0.05); strong outward rectification; slow activation at positive potentials, rapid inactivation at negative potentials; activated and subsequently desensitized by [Ca2+]I
Comment	–	TRPM5 is not blocked by ATP

Nomenclature	TRPM6	TRPM7
HGNC, UniProt	TRPM6, Q9BX84	TRPM7, Q96QT4
Other chemical activators	constitutively active, activated by reduction of intracellular Mg2+	activation of PKA
Endogenous activators (EC50)	extracellular H+ (Potentiation, μM range), intracellular Mg2+	intracellular ATP (Potentiation), cAMP (elevated cAMP levels), Extracellular H+ (Potentiation)
Activators (EC50)	2-APB (Potentiation)	2-APB (mM range)
Endogenous channel blockers (IC50)	Mg2+ (inward current mediated by monovalent cations is blocked) (1.1x10-6 – 3.4x10-6 M), Ca2+ (inward current mediated by monovalent cations is blocked) (4.8x10-6 – 5.4x10-6 M)	Mg2+
Channel Blockers (IC50)	ruthenium red (1x10-7 M) [voltage dependent -120.0 mV]	2-APB (μM range), carvacrol, La3+, spermine (permeant blocker)
Functional characteristics	γ = 40–87 pS; permeable to mono- and di-valent cations with a preference for divalents (Mg2+ > Ca2+; PCa/PNa = 6.9), conductance sequence Zn2+ > Ba2+ > Mg2+ = Ca2+ = Mn2+ > Sr2+ > Cd2+> Ni2+; strong outward rectification abolished by removal of extracellular divalents, inhibited by intracellular Mg2+ (IC50 = 0.5 mM) and ATP	γ = 40-105 pS at negative and positive potentials respectively; conducts mono-and di-valent cations with a preference for monovalents (PCa/PNa = 0.34); conductance sequence Ni2+ > Zn2+ > Ba2+ = Mg2+ > Ca2+ = Mn2+ > Sr2+ > Cd2+; outward rectification, decreased by removal of extracellular divalent cations; inhibited by intracellular Mg2+, Ba2+, Sr2+, Zn2+, Mn2+ and Mg.ATP (disputed); activated by and intracellular alkalinization; sensitive to osmotic gradients

Nomenclature	HGNC, UniProt	Other chemical activators	Physical activators	Activators (EC50)	Channel Blockers (IC50)	Functional characteristics	Comment
TRPM8	TRPM8, Q7Z2W7	agonist activities are temperature dependent and potentiated by cooling	depolarization (V½ ∼ +50 mV at 15°C), cooling (< 22–26°C)	icilin (requires intracellular Ca2+ as a co-factor for full agonist activity), (-)-menthol (inhibited by intracellular Ca2+), WS-12	2-APB, 5-benzyloxytryptamine, ACAA, AMTB 286, anandamide, BCTC, cannabidiol, capsazepine, clotrimazole, Δ9-tetrahydrocannabinol, La3+, linoleic acid, NADA	γ = 40-83 pS at positive potentials; conducts mono- and di-valent cations non-selectively (PCa/PNa = 1.0–3.3); pronounced outward rectification; demonstrates densensitization to chemical agonists and adaptation to a cold stimulus in the presence of Ca2+; modulated by lysophospholipids and PUFAs	cannabidiol and Δ9-tetrahydrocannabinol are examples of cannabinoids. TRPM8 is insensitive to ruthenium red

Nomenclature	HGNC, UniProt	Other chemical activators	Physical activators	Activators (EC50)	Channel Blockers (IC50)	Functional characteristics
TRPA1	TRPA1, O75762	isothiocyanates (covalent) and 1,4-dihydropyridines (non-covalent)	cooling (<17°C) (disputed)	chlorobenzylidene malononitrile (Activation, covalent), cinnamaldehyde (Activation, covalent), formalin (Activation, covalent), icilin (Activation, non-covalent), (-)-menthol (Activation, non-covalent) (Concentration range = 1x10-6 - 1x10-4 M), thymol (Activation, non-covalent) (Concentration range = 1x10-6 - 1x10-4 M), acrolein (Agonist, covalent) (5.011x10-6 M) [Physiological voltage] 238, allicin (Agonist, covalent) (7.943x10-6 M) [Physiological voltage] 239, Δ9-tetrahydrocannabinol (Agonist, non-covalent) (1.259x10-5 M) [-60.0 mV] 272, nicotine (Activation, non-covalent) (∼2x10-5 M), URB597 (Agonist, non-covalent) (2.4x10-5 M) 306	ruthenium red (Inhibition) (<1x10-6 – 3x10-6 M), AP18 (Inhibition) (3.1x10-6 M) 319, HC030031 (Inhibition) (6.2x10-6 M) 296	γ = 87–100 pS; conducts mono- and di-valent cations non-selectively (PCa/PNa = 0.84); outward rectification; activated by elevated intracellular Ca2+

Nomenclature	TRPV1	TRPV2	TRPV3	TRPV4
HGNC, UniProt	TRPV1, Q8NER1	TRPV2, Q9Y5S1	TRPV3, Q8NET8	TRPV4, Q9HBA0
Other chemical activators	NO-mediated cysteine S-nitrosylation	–	NO-mediated cysteine S-nitrosylation	epoxyeicosatrieonic acids and NO-mediated cysteine S-nitrosylation
Physical activators	depolarization (V½ ∼ 0 mV at 35°C), noxious heat (> 43°C at pH 7.4)	noxious heat (> 35°C; rodent, not human) 305	depolarization (V½ ∼ +80 mV, reduced to more negative values following heat stimuli), heat (23°C - 39°C, temperature threshold reduces with repeated heat challenge)	constitutively active, heat (> 24°C - 32°C), mechanical stimuli
Endogenous activators (EC50)	12S-HPETE, 15S-HPETE, 5S-HETE, LTB4, Extracellular H+ (at 37°C) (3.98x10-6 M)	–	–	–
Activators (EC50)	camphor, capsaicin, diphenylboronic anhydride, DkTx (Irreversible agonist), olvanil, phenylacetylrinvanil, resiniferatoxin	Δ9-tetrahydrocannabinol, diphenylboronic anhydride, probenecid, 2-APB (1x10-5 M - Rat) 305,326, cannabidiol (Activation) (3.17x10-5 M) 326	2-APB, 6-tert-butyl-m-cresol, camphor, carvacrol, diphenylboronic anhydride, eugenol, incensole acetate, (-)-menthol, thymol	4α-PDD, 4α-PDH, bisandrographolide, phorbol 12-myristate 13-acetate, GSK1016790A (2.1x10-9 M) 336, RN1747 (7.7x10-7 M) 341
Selective activators (EC50)	–	2-APB (Agonist) (Mouse) [Physiological voltage] 270,273,297,298	–	–
Channel Blockers (IC50)	2-APB, allicin, anandamide, NADA, SB452533, AMG517 (9x10-10 M), 5'-iodoresiniferatoxin (3.9x10-9 M), AMG628 (3.7x10-9 M), SB705498 (3x10-9 – 6x10-9 M), A425619 (5x10-9 M), A778317 (5x10-9 M), 6-iodo-nordihydrocapsaicin (1x10-8 M), JYL1421 (9.2x10-9 M), BCTC (6x10-9 – 3.5x10-8 M), SB366791 (1.8x10-8 M), JNJ17203212 (6.5x10-8 M), capsazepine (4x10-8 – 2.8x10-7 M), ruthenium red (9x10-8 – 2.2x10-7 M)	amiloride, La3+, SKF96365, TRIM, ruthenium red (6x10-7 M)	diphenyltetrahydrofuran (Concentration range = 6x10-6 - 1x10-5 M), ruthenium red (Concentration range = < 1x10-6 M)	Gd3+, La3+, ruthenium red [voltage dependent], HC067047 (1.7x10-8 M) 256, RN1734 (2.3x10-6 M) 341
Radioligands (Kd)	[125I]resiniferatoxin, [3H]resiniferatoxin, [3H]A778317 (3.4x10-9 M)	–	–	–
Functional characteristics	γ = 35 pS at – 60 mV; 77 pS at + 60 mV, conducts mono and di-valent cations with a selectivity for divalents (PCa/PNa = 9.6); voltage- and time- dependent outward rectification; potentiated by ethanol; activated/potentiated/upregulated by PKC stimulation; extracellular acidification facilitates activation by PKC; desensitisation inhibited by PKA; inhibited by Ca2+/ calmodulin; cooling reduces vanilloid-evoked currents; may be tonically active at body temperature	Conducts mono- and di-valent cations (PCa/PNa = 0.9–2.9); dual (inward and outward) rectification; current increases upon repetitive activation by heat; translocates to cell surface in response to IGF-1 to induce a constitutively active conductance, translocates to the cell surface in response to membrane stretch	γ = 197 pS at = +40 to +80 mV, 48 pS at negative potentials; conducts mono- and di-valent cations; outward rectification; potentiated by arachidonic acid	γ = ∼60 pS at –60 mV, ∼90-100 pS at +60 mV; conducts mono- and di-valent cations with a preference for divalents (PCa/PNa = 6–10); dual (inward and outward) rectification; potentiated by intracellular Ca2+ via Ca2+/ calmodulin; inhibited by elevated intracellular Ca2+ via an unknown mechanism (IC50 = 0.4 μM)

Nomenclature	TRPV5	TRPV6
HGNC, UniProt	TRPV5, Q9NQA5	TRPV6, Q9H1D0
Activators	constitutively active (with strong buffering of intracellular Ca2+)	constitutively active (with strong buffering of intracellular Ca2+)
Activators (EC50)	–	2-APB (Potentiation)
Other channel blockers	Pb2+ = Cu2+ = Gd3+ > Cd2+ > Zn2+ > La3+ > Co2+ > Fe2+	–
Channel Blockers (IC50)	econazole, Mg2+, miconazole, ruthenium red (1.21x10-7 M)	Cd2+, La3+, Mg2+, ruthenium red (9x10-6 M)
Functional characteristics	γ = 59–78 pS for monovalent ions at negative potentials, conducts mono- and di-valents with high selectivity for divalents (PCa/PNa > 107); voltage- and time- dependent inward rectification; inhibited by intracellular Ca2+ promoting fast inactivation and slow downregulation; feedback inhibition by Ca2+ reduced by calcium binding protein 80-K-H; inhibited by extracellular and intracellular acidosis; upregulated by 1,25-dihydrovitamin D3	γ = 58–79 pS for monovalent ions at negative potentials, conducts mono- and di-valents with high selectivity for divalents (PCa/PNa > 130); voltage- and time-dependent inward rectification; inhibited by intracellular Ca2+ promoting fast and slow inactivation; gated by voltage-dependent channel blockade by intracellular Mg2+; slow inactivation due to Ca2+-dependent calmodulin binding; phosphorylation by PKC inhibits Ca2+-calmodulin binding and slow inactivation; upregulated by 1,25-dihydroxyvitamin D3

Nomenclature	TRPML1	TRPML2	TRPML3
HGNC, UniProt	MCOLN1, Q9GZU1	MCOLN2, Q8IZK6	MCOLN3, Q8TDD5
Activators	TRPML1Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)	TRPML2Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)	TRPML3Va: Constitutively active, current inhibited by extracellular acidification (equivalent to intralysosomal acidicification), Wild type TRPML3: Activated by Na+-free extracellular (extracytosolic) solution and membrane depolarization, current inhibited by extracellular acidification (equivalent to intralysosomal acidicification)
Channel Blockers (IC50)	–	–	Gd3+
Functional characteristics	TRPML1Va: γ = 40 pS and 76-86 pS at very negative holding potentials with Fe2+ and monovalent cations as charge carriers, respectively; conducts Na+≅ K+>Cs+ and divalent cations (Ba2+>Mn2+>Fe2+>Ca2+> Mg2+> Ni2+>Co2+> Cd2+>Zn2+>>Cu2+) protons; monovalent cation flux suppressed by divalent cations (e.g. Ca2+, Fe2+); inwardly rectifying	TRPML1Va: Conducts Na+; monovalent cation flux suppressed by divalent cations; inwardly rectifying	TRPML3Va: γ = 49 pS at very negative holding potentials with monovalent cations as charge carrier; conducts Na+ > K+ > Cs+ with maintained current in the presence of Na+, conducts Ca2+ and Mg2+, but not Fe2+, impermeable to protons; inwardly rectifying Wild type TRPML3: γ = 59 pS at negative holding potentials with monovalent cations as charge carrier; conducts Na+ > K+ > Cs+ and Ca2+ (PCa/PK ≅ 350), slowly inactivates in the continued presence of Na+ within the extracellular (extracytosolic) solution; outwardly rectifying

Nomenclature	TRPP2	TRPP3
HGNC, UniProt	PKD2L1, Q9P0L9	PKD2L2, Q9NZM6
Activators	Low constitutive activity, enhanced by membrane depolarization; changes in cell volume affect voltage-dependent gating (increased channel opening probability with cell swelling)	–
Channel Blockers (IC50)	flufenamate, Gd3+, La3+, phenamil (1.4x10-7 M), benzamil (1.1x10-6 M), EIPA (1.05x10-5 M), amiloride (1.43x10-4 M)	–
Functional characteristics	γ = 105–137 pS (outward conductance) 184–399 pS (inward conductance), conducts mono- and di-valent cations with a preference for divalents (PCa/PNa = 4.0–4.3); steady state currents rectify outwardly, whereas instantaneous currents show strong inward rectification; activated and subsequently inactivated by intracellular Ca2+ (human, but not mouse); inhibited by extracellular acidification and potentiated by extracellular alkalization	–

Nomenclature	Cav1.1	Cav1.2	Cav1.3	Cav1.4	Cav2.1
HGNC, UniProt	CACNA1S, Q13698	CACNA1C, Q13936	CACNA1D, Q01668	CACNA1F, O60840	CACNA1A, O00555
Activators (EC50)	FPL64176, (-)-(S)-BayK8644, SZ(+)-(S)-202-791	FPL64176, (-)-(S)-BayK8644, SZ(+)-(S)-202-791	(-)-(S)-BayK8644	(-)-(S)-BayK8644	–
Channel Blockers (IC50)	calciseptine, diltiazem, nifedipine, verapamil	calciseptine, diltiazem, nifedipine, verapamil	verapamil (less sensitive to dihydropyridine antagonists)	–	ω-agatoxin IVB, ω-conotoxin MVIIC, ω-agatoxin IVA (P current component) (∼1x10-9 M), ω-agatoxin IVA (Q current component) (∼9x10-8 M)
Functional characteristics	High voltage-activated, slow inactivation	High voltage-activated, slow inactivation (Ca2+ dependent)	Low-moderate voltage-activated, slow inactivation (Ca2+ dependent)	Moderate voltage-activated, slow inactivation (Ca2+ independent)	Moderate voltage-activated, moderate inactivation
Comment	nifedipine, diltiazem, verapamil and calciseptine are examples of dihydropyridine antagonists	nifedipine, diltiazem, verapamil and calciseptine are examples of dihydropyridine antagonists	verapamil is an example of a dihydropyridine antagonist	Cav1.4 is less sensitive to dihydropyridine antagonists	–

Nomenclature	Cav2.2	Cav3.1	Cav3.2	Cav3.3
HGNC, UniProt	CACNA1B, Q00975	CACNA1G, O43497	CACNA1H, O95180	CACNA1I, Q9P0X4
Channel Blockers (IC50)	ω-conotoxin GVIA, ω-conotoxin MVIIC	kurtoxin, mibefradil, Ni2+ (low sensitivity to Ni2+), SB209712	kurtoxin, mibefradil, Ni2+ (high sensitivity to Ni2+), SB209712	kurtoxin, mibefradil, Ni2+ (low sensitivity to Ni2+), SB209712
Functional characteristics	High voltage-activated, moderate inactivation	Low voltage-activated, fast inactivation	Low voltage-activated, fast inactivation	Low voltage-activated, moderate inactivation

Nomenclature	HGNC, UniProt	Channel Blockers (IC50)	Functional characteristics
Hv1	HVCN1, Q96D96	Zn2+ (∼5x10-7 – 2x10-6 M), Cd2+ (∼1x10-5 M)	Activated by membrane depolarization mediating macroscopic currents with time-, voltage- and pH-dependence; outwardly rectifying; voltage dependent kinetics with relatively slow current activation sensitive to extracellular pH and temperature, relatively fast deactivation; voltage threshold for current activation determined by pH gradient (ΔpH = pHo -pHi) across the membrane

Nomenclature	Nav1.1	Nav1.2	Nav1.3	Nav1.4	Nav1.5	Nav1.6	Nav1.7	Nav1.8	Nav1.9
HGNC, UniProt	SCN1A, P35498	SCN2A, Q99250	SCN3A, Q9NY46	SCN4A, P35499	SCN5A, Q14524	SCN8A, Q9UQD0	SCN9A, Q15858	SCN10A, Q9Y5Y9	SCN11A, Q9UI33
Activators (EC50)	batrachotoxin, veratridine	batrachotoxin, veratridine	batrachotoxin, veratridine	batrachotoxin, veratridine	batrachotoxin, veratridine	batrachotoxin, veratridine	batrachotoxin, veratridine	–	–
Channel Blockers (IC50)	saxitoxin, tetrodotoxin (Concentration range = 1x10-8 M)	saxitoxin,tetrodotoxin (Concentration range = 1x10-8 M)	saxitoxin, tetrodotoxin (Concentration range = 2x10-9 - 1.5x10-8 M)	μ-conotoxin GIIIA, saxitoxin, tetrodotoxin (Concentration range = 5x10-9 M)	tetrodotoxin (Concentration range = 2x10-6 M)	saxitoxin, tetrodotoxin (Concentration range = 6x10-9 M)	saxitoxin, tetrodotoxin (Concentration range = 4x10-9 M)	tetrodotoxin (Concentration range = 6x10-5 M)	tetrodotoxin (Concentration range = 4x10-5 M)
Functional characteristics	Fast inactivation (0.7 ms)	Fast inactivation (0.8 ms)	Fast inactivation (0.8 ms)	Fast inactivation (0.6 ms)	Fast inactivation (1 ms)	Fast inactivation (1 ms)	Fast inactivation (0.5 ms)	Slow inactivation (6 ms)	Slow inactivation (16 ms)