The Concise Guide to PHARMACOLOGY 2013/14: ligand-gated 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. Ligand-gated ion channels are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, 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 Ligand-gated Ion Channels

Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for the permeant ions. The channels are opened, or gated, by the binding of a neurotransmitter to an orthosteric site(s) that triggers a conformational change that results in the conducting state. Modulation of gating can occur by the binding of endogenous, or exogenous, modulators to allosteric sites. LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction. Such transmission involves the release of a neurotransmitter from a pre-synaptic neurone and the subsequent activation of post-synaptically located receptors that mediate a rapid, phasic, electrical signal (the excitatory, or inhibitory, post-synaptic potential). However, In addition to their traditional role in phasic neurotransmission, it is now established that some LGICs mediate a tonic form of neuronal regulation that results from the activation of extra-synaptic receptors by ambient levels of neurotransmitter. The expression of some LGICs by non-excitable cells is suggestive of additional functions.

By convention, the LGICs comprise the excitatory, cation-selective, nicotinic acetylcholine (Millar and Gotti, 2009; Changeux, 2010), 5-HT3 (Barnes et al., 2009; Walstab et al., 2010), ionotropic glutamate (Lodge, 2009; Traynelis et al., 2010) and P2X receptors (Jarvis and Khakh, 2009; Surprenant and North, 2009) and the inhibitory, anion-selective, GABAA (Olsen and Sieghart, 2008; Belelli et al., 2009) and glycine receptors (Lynch, 2009; Yevenes and Zeihofer, 2011). The nicotinic acetylcholine, 5-HT3, GABAA and glycine receptors (and an additional zinc-activated channel) are pentameric structures and are frequently referred to as the Cys-loop receptors due to the presence of a defining loop of residues formed by a disulphide bond in the extracellular domain of their constituent subunits (Miller and Smart, 2010; Thompson et al., 2010). However, the prokaryotic ancestors of these receptors contain no such loop and the term pentameric ligand-gated ion channel (pLGIC) is gaining acceptance in the literature (Hilf and Dutzler, 2009). The ionotropic glutamate and P2X receptors are tetrameric and trimeric structures, respectively. Multiple genes encode the subunits of LGICs and the majority of these receptors are heteromultimers. Such combinational diversity results, within each class of LGIC, in a wide range of receptors with differing pharmacological and biophysical properties and varying patterns of expression within the nervous system and other tissues. The LGICs thus present attractive targets for new therapeutic agents with improved discrimination between receptor isoforms and a reduced propensity for off-target effects. The development of novel, faster screening techniques for compounds acting on LGICs (Dunlop et al., 2008) will greatly aid in the development of such agents.

Nomenclature	5-HT3A	5-HT3AB
Subunits	5-HT3A (HTR3A, P46098)	5-HT3A, 5-HT3B (HTR3B, O95264)
Selective agonists (EC50)	SR57227A (∼4x10-7 M), meta-chlorphenylbiguanide (1.6x10-6 – 4x10-6 M) 4,8,24,28,29, 2-methyl-5-HT (2.5x10-6 – 3.1x10-6 M) 4,8,24,28, 1-phenylbiguanide (8x10-5 M) 4	–
Selective antagonists (IC50)	(S)-zacopride (Ki 1x10-9 M) 5, granisetron (Ki ∼1.5x10-9 – 2.5x10-9 M) 15,28, tropisetron (Ki 1.5x10-9 – 3x10-9 M) 24,28, ondansetron (Ki ∼5x10-9 – 1.5x10-8 M) 5,15,28	–
Channel Blockers (IC50)	picrotoxinin (1.1x10-5 M) 42, TMB-8 (1.176x10-5 M) 41, diltiazem (2.1x10-5 M) 42, bilobalide (4.7x10-4 M) 42, ginkgolide B (7.3x10-4 M) 42	picrotoxinin (6.3x10-5 M) 43, bilobalide (3.1x10-3 M) 43, ginkgolide B (3.9x10-3 M) 43
Radioligands (Kd)	[3H]ramosetron (Antagonist) (1.5x10-10 M) 28, [3H]GR65630 (Antagonist) (2.56x10-9 – 4.8x10-10 M) 12,24, [3H]granisetron (Antagonist) (1.2x10-9 M) 5,15, [3H](S)-zacopride (Antagonist) (2x10-9 M) 35, [3H]LY278584 (Antagonist) (3.08x10-9 M) 1	–
Functional characteristics	γ = 0.4-0.8 pS [+ 5-HT3B, γ = 16 pS]; inwardly rectifying current [+ 5-HT3B, rectification reduced]; nH 2-3 [+ 5-HT3B 1-2]; relative permeability to divalent cations reduced by co-expression of the 5-HT3B subunit	γ = 0.4-0.8 pS [+ 5-HT3B, γ = 16 pS]; inwardly rectifying current [+ 5-HT3B, rectification reduced]; nH 2-3 [+ 5-HT3B 1-2]; relative permeability to divalent cations reduced by co-expression of the 5-HT3B subunit

Nomenclature	α1	α2	α3	α4	α5	α6
HGNC, UniProt	GABRA1, P14867	GABRA2, P47869	GABRA3, P34903	GABRA4, P48169	GABRA5, P31644	GABRA6, Q16445
Agonists	isoguvacine [GABA site] (Full agonist), isonipecotic acid [GABA site], muscimol [GABA site] (Full agonist), piperidine-4-sulphonic acid [GABA site] (Full agonist), THIP [GABA site]
Selective antagonists	bicuculline [GABA site], gabazine [GABA site]
Channel Blockers	picrotoxin, TBPS
Endogenous allosteric regulators	5α-pregnan-3α-ol-20-one (Potentiation), tetrahydrodeoxycorticosterone (Potentiation), Zn2+ (Inhibition)
Allosteric Regulators [benzodiazepine site]	α3IA (Inverse agonist), α5IA (Inverse agonist), bretazenil (Full agonist), diazepam (Full agonist), DMCM (Inverse agonist), flumazenil (Antagonist), flunitrazepam (Full agonist), MRK016 (Inverse agonist), Ro154513 (Inverse agonist), Ro194603 (Inverse agonist), Ro4938581 (Inverse agonist), TP003 (Antagonist), TPA023 (Antagonist)	α3IA (Inverse agonist), α5IA (Inverse agonist), bretazenil (Full agonist), diazepam (Full agonist), DMCM (Inverse agonist), flumazenil (Antagonist), flunitrazepam (Full agonist), MRK016 (Inverse agonist), ocinaplon (Partial agonist), Ro154513 (Inverse agonist), Ro194603 (Inverse agonist), Ro4938581 (Inverse agonist), TP003 (Antagonist), ZK93426 (Antagonist)	α5IA (Inverse agonist), bretazenil (Full agonist), diazepam (Full agonist), DMCM (Inverse agonist), flumazenil (Antagonist), flunitrazepam (Full agonist), MRK016 (Inverse agonist), ocinaplon (Partial agonist), Ro154513 (Inverse agonist), Ro4938581 (Inverse agonist), ZK93426 (Antagonist)	flumazenil (Partial agonist, low affinity)	α3IA (Inverse agonist), bretazenil (Full agonist), diazepam (Full agonist), DMCM (Inverse agonist), flumazenil (Antagonist), flunitrazepam (Full agonist), ocinaplon (Partial agonist), Ro154513 (Inverse agonist), Ro194603 (Inverse agonist), TP003 (Antagonist), TPA023 (Antagonist), ZK93426 (Antagonist)	bretazenil (Full agonist), flumazenil (Partial agonist, low affinity)
Selective allosteric regulators [benzodiazepine site]	indiplon (Full agonist, high affinity), L838417 (Antagonist), ocinaplon (Full agonist), zaleplon (Full agonist, high affinity), ZK93426 (Antagonist), zolpidem (Full agonist, high affinity)	L838417 (Partial agonist), TPA023 (Partial agonist, low efficacy)	α3IA (higher affinity), L838417 (Partial agonist), Ro194603 (Inverse agonist, higher affinity), TP003 (Partial agonist, high efficacy), TPA023 (Partial agonist, low efficacy)	bretazenil (Full agonist), Ro154513 (Full agonist)	α5IA (Inverse agonist), L655708 (Inverse agonist, high affinity), L838417 (Partial agonist), MRK016 (Inverse agonist), Ro4938581 (Inverse agonist, higher affinity), RY024 (Inverse agonist, high affinity)	Ro154513 (Full agonist)
Radioligands (Kd)	[11C]flumazenil [benzodiazepine site], [18F]fluoroethylflumazenil [benzodiazepine site], [35S]TBPS [anion channel], [3H]CGS8216 [benzodiazepine site], [3H]flunitrazepam [benzodiazepine site], [3H]gabazine [GABA site], [3H]muscimol [GABA site], [3H]zolpidem [benzodiazepine site]
Comment	Zn2+ is an endogenous allosteric regulator and causes potent inhibition of receptors formed from binary combinations of α and β subunits, incorporation of a δ or γ subunit causes a modest, or pronounced, reduction in inhibitory potency, respectively 77

Nomenclature	β1	β2	β3	γ1	γ2	γ3
HGNC, UniProt	GABRB1, P18505	GABRB2, P47870	GABRB3, P28472	GABRG1, Q8NIC3	GABRG2, P18507	GABRG3, Q99928
Channel Blockers	picrotoxin, TBPS
Comment	Zn2+ is an endogenous allosteric regulator and causes potent inhibition of receptors formed from binary combinations of α and β subunits, incorporation of a δ or γ subunit causes a modest, or pronounced, reduction in inhibitory potency, respectively 77

Nomenclature	δ	ε	θ	π
HGNC, UniProt	GABRD, O14764	GABRE, P78334	GABRQ, Q9UN88	GABRP, O00591
Selective agonists	THIP [GABA site] (Full agonist)	–	–	–
Channel Blockers	picrotoxin, TBPS
Comment	Zn2+ is an endogenous allosteric regulator and causes potent inhibition of receptors formed from binary combinations of α and β subunits, incorporation of a δ or γ subunit causes a modest, or pronounced, reduction in inhibitory potency, respectively

Nomenclature	ρ1	ρ2	ρ3
HGNC, UniProt	GABRR1, P24046	GABRR2, P28476	GABRR3, A8MPY1
Agonists	isoguvacine [GABA site] (Partial agonist), muscimol [GABA site] (Partial agonist)
Selective agonists	5-Me-IAA [GABA site] (Full agonist), (±)-cis-2-CAMP [GABA site] (Full agonist)
Antagonists	isonipecotic acid [GABA site], piperidine-4-sulphonic acid [GABA site], THIP [GABA site]
Selective antagonists	aza-THIP [GABA site], cis-3-ACPBPA [GABA site], trans-3-ACPBPA [GABA site], TPMPA [GABA site]
Channel Blockers	picrotoxin, TBPS
Comment	bicuculline is not active at these subunits

Nomenclature	α1	α2	α3
HGNC, UniProt	GLRA1, P23415	GLRA2, P23416	GLRA3, O75311
Selective agonists (potency order)	glycine > β-alanine > taurine	glycine > β-alanine > taurine	glycine > β-alanine > taurine
Selective antagonists (IC50)	HU-308 (weak inhibition), PMBA, strychnine, pregnenolone sulphate (Ki 1.9x10-6 M), tropisetron (Ki 8.4x10-5 M), ginkgolide X (7.6x10-7 M), nifedipine (3.3x10-6 M), bilobalide (2x10-5 M), colchicine (3.24x10-4 M)	PMBA, strychnine, pregnenolone sulphate (Ki 5.5x10-6 M), tropisetron (Ki 1.3x10-5 M), HU-210 (9x10-8 M), WIN55212-2 (2.2x10-7 M), HU-308 (1.1x10-6 M), ginkgolide X (2.8x10-6 M), bilobalide (8x10-6 M), colchicine (6.4x10-5 M), 5,7-dichlorokynurenic acid (1.88x10-4 M)	strychnine, HU-210 (5x10-8 M), HU-308 (9.7x10-8 M), WIN55212-2 (9.7x10-8 M), (12E,20Z,18S)-8-hydroxyvariabilin (7x10-6 M), nifedipine (2.92x10-5 M)
Channel Blockers (IC50)	cyanotriphenylborate (1.3x10-6 M), ginkgolide B (6x10-7 – 8x10-6 M), picrotin (5.2x10-6 M), picrotoxinin (5.1x10-6 M), picrotoxin (6.3x10-6 M)	picrotoxinin (4.1x10-7 M), picrotoxin (2.3x10-6 M), ginkgolide B (3.7x10-6 – 1.14x10-5 M), picrotin (1.31x10-5 M), cyanotriphenylborate (>2x10-5 M)	picrotoxin (block is weaker when β subunit is co-expressed), picrotoxinin (4.3x10-7 M), ginkgolide B (1.8x10-6 M), picrotin (6x10-6 M)
Endogenous allosteric regulators	Extracellular H+ (Inhibition, endogenous), Zn2+ (Potentiation, endogenous; not affected by β subunit co-expression) (EC50 3.7x10-8 M), Cu2+ (Inhibition, endogenous; not affected by β subunit co-expression) (IC50 4x10-6 – 1.5x10-5 M), Zn2+ (Inhibition, endogenous) (IC50 1.5x10-5 M)	Zn2+ (Potentiation, endogenous; not affected by β subunit co-expression) (EC50 5.4x10-7 M), Cu2+ (Inhibition, endogenous) (IC50 1.7x10-5 M), Zn2+ (Inhibition, endogenous) (IC50 3.6x10-4 M)	Cu2+ (Inhibition, endogenous) (IC50 9x10-6 M), Zn2+ (Inhibition, endogenous) (IC50 1.5x10-4 M)
Selective allosteric regulators	anandamide (Potentiation) (EC50 3.8x10-8 M), HU-210 (Potentiation) (EC50 2.7x10-7 M), Δ9-tetrahydrocannabinol (Potentiation, ∼1500% potentiation) (EC50 ∼3x10-6 M)	Δ9-tetrahydrocannabinol (Potentiation, ∼230% potentiation) (EC50 ∼1x10-6 M)	Δ9-tetrahydrocannabinol (Potentiation, ∼1500% potentiation) (EC50 ∼5x10-6 M)
Radioligands (Kd)	[3H]strychnine	[3H]strychnine	[3H]strychnine
Functional characteristics	γ = 86 pS (main state); (+ β = 44 pS)	γ = 111 pS (main state); (+ β = 54 pS)	γ = 105 pS (main state); (+ β = 48)

Nomenclature	GluA1	GluA2	GluA3	GluA4
HGNC, UniProt	GRIA1, P42261	GRIA2, P42262	GRIA3, P42263	GRIA4, P48058
Agonists	AMPA (Full agonist), (S)-5-fluorowillardiine (Full agonist)
Selective antagonists	ATPO, GYKI53655, GYKI53784 (active isomer, non-competitive), LY293558, NBQX
Channel Blockers	extracellular argiotoxin, extracellular joro toxin	extracellular argiotoxin	extracellular argiotoxin, extracellular joro toxin	extracellular argiotoxin, extracellular joro toxin
Allosteric Regulators	aniracetam (Positive), CX516 (Positive), CX546 (Positive), cyclothiazide (Positive), IDRA-21 (Positive), LY392098 (Positive), LY404187 (Positive), LY503430 (Positive), piracetam (Positive), S18986 (Positive)
Radioligands (Kd)	[3H]AMPA, [3H]CNQX
Comment	piracetam and aniracetam are examples of pyrrolidinones. cyclothiazide, S18986, and IDRA-21 are examples of benzothiadiazides. CX516 and CX546 are examples of benzylpiperidines. LY392098, LY404187 and LY503430 are examples of biarylpropylsulfonamides. Also blocked by intracellular polyamines

Nomenclature	GluK1	GluK2	GluK3	GluK4	GluK5
HGNC, UniProt	GRIK1, P39086	GRIK2, Q13002	GRIK3, Q13003	GRIK4, Q16099	GRIK5, Q16478
Agonists (EC50)	8-deoxy-neodysiherbaine (Full agonist), ATPA (Full agonist), domoic acid (Full agonist), dysiherbaine (Full agonist), (S)-4-AHCP (Full agonist), (S)-5-iodowillardiine, kainate (Full agonist), LY339434 (Full agonist), SYM2081 (Full agonist)	domoic acid (Full agonist), dysiherbaine (Full agonist), kainate (Full agonist), SYM2081 (Full agonist)	dysiherbaine (Full agonist), kainate (Full agonist, low potency), SYM2081 (Full agonist)	domoic acid (Full agonist), dysiherbaine (Full agonist), kainate (Full agonist), SYM2081 (Full agonist)	domoic acid (Full agonist), dysiherbaine (Full agonist), kainate (Full agonist), SYM2081 (Full agonist)
Selective antagonists (IC50)	2,4-epi-neodysiherbaine, ACET, LY382884, LY466195, MSVIII-19, NS3763 (non-competitive), UBP302, UBP310	2,4-epi-neodysiherbaine	–	–	–
Allosteric Regulators	concanavalin A (Positive)	concanavalin A (Positive)	–	–	–
Radioligands (Kd)	[3H](2S,4R)-4-methylglutamate, [3H]kainate, [3H]UBP310 (2.1x10-8 M) 138	[3H](2S,4R)-4-methylglutamate, [3H]kainate	[3H](2S,4R)-4-methylglutamate, [3H]kainate, [3H]UBP310 (5.6x10-7 M) 138	[3H](2S,4R)-4-methylglutamate, [3H]kainate	[3H](2S,4R)-4-methylglutamate, [3H]kainate
Comment	–	Intracellular polyamines are subtype selective channel blockers (GluK3 >> GluK2)	domoic acid and concanavalin A are inactive at the GluK3 subunit. Intracellular polyamines are subtype selective channel blockers (GluK3 >> GluK2)	–	–

Nomenclature	GluN1	GluN2A	GluN2B	GluN2C
HGNC, UniProt	GRIN1, Q05586	GRIN2A, Q12879	GRIN2B, Q13224	GRIN2C, Q01098
Endogenous agonists	D-aspartate [glutamate site], D-serine [glycine site], glycine [glycine site], L-aspartate [glutamate site]	D-aspartate [glutamate site] (low potency), D-serine [glycine site] (low potency), glycine [glycine site] (low potency), L-aspartate [glutamate site] (low potency)	D-aspartate [glutamate site] (intermediate potency), D-serine [glycine site] (intermediate potency), glycine [glycine site] (intermediate potency), L-aspartate [glutamate site] (intermediate potency)	D-aspartate [glutamate site] (intermediate potency), D-serine [glycine site] (intermediate potency), glycine [glycine site] (intermediate potency), L-aspartate [glutamate site] (intermediate potency)
Agonists	(+)-HA966 [glycine site] (Partial agonist), homoquinolinic acid [glutamate site] (Partial agonist), (RS)-(tetrazol-5-yl)glycine [glutamate site] (Full agonist), NMDA [glutamate site] (Full agonist)	(+)-HA966 [glycine site] (Partial agonist, low potency), homoquinolinic acid [glutamate site] (partial agonist), (RS)-(tetrazol-5-yl)glycine [glutamate site] (Full agonist, low potency), NMDA [glutamate site] (Full agonist, low potency)	(+)-HA966 [glycine site] (Partial agonist), homoquinolinic acid [glutamate site] (Full agonist, high potency), (RS)-(tetrazol-5-yl)glycine [glutamate site] (Full agonist, intermediate potency), NMDA [glutamate site] (Full agonist, intermediate potency)	homoquinolinic acid [glutamate site] (partial agonist), (RS)-(tetrazol-5-yl)glycine [glutamate site] (Full agonist, intermediate potency), NMDA [glutamate site] (Full agonist, intermediate potency)
Selective antagonists	5,7-dichlorokynurenic acid [glycine site], GV196771A [glycine site], L689560 [glycine site], L701324 [glycine site]	5,7-dichlorokynurenic acid [glycine site], CGP37849 [glutamate site], CGS19755 [glutamate site], conantokin-G [glutamate site] (low potency), d-AP5 [glutamate site], d-CCPene [glutamate site] (high potency), GV196771A [glycine site], L689560 [glycine site], L701324 [glycine site], LY233053 [glutamate site], NVP-AAM077 [glutamate site] (high potency (human), but weakly selective for rat GluN2A versus GluN2B) 139,155,156,183, UBP141 [glutamate site] (low potency) 180	5,7-dichlorokynurenic acid [glycine site], CGP37849 [glutamate site], CGS19755 [glutamate site], conantokin-G [glutamate site] (high potency), d-AP5 [glutamate site], d-CCPene [glutamate site] (high potency), GV196771A [glycine site], L689560 [glycine site], L701324 [glycine site], LY233053 [glutamate site], NVP-AAM077 [glutamate site] (low potency (human), but weakly selective for rat GluN2A versus GluN2B) 139,155,156,183, UBP141 [glutamate site] (low potency) 180	5,7-dichlorokynurenic acid [glycine site], CGP37849 [glutamate site], CGS19755 [glutamate site], conantokin-G [glutamate site] (intermediate potency), d-AP5 [glutamate site], d-CCPene [glutamate site] (intermediate potency), GV196771A [glycine site], L689560 [glycine site], L701324 [glycine site], LY233053 [glutamate site], UBP141 [glutamate site] (intermediate potency) 180
Channel Blockers	–	amantidine (GluN2C = GluN2D ≥ GluN2B ≥ GluN2A), ketamine, memantine (GluN2C ≥ GluN2D ≥ GluN2B > GluN2A), Mg2+ (GluN2A = GluN2B > GluN2C = GluN2D), MK-801, N1-dansyl-spermine (GluN2A = GluN2B >> GluN2C = GluN2D), phencyclidine
Radioligands (Kd)	[3H]CGP39653 [glutamate site], [3H]CGP61594 [glycine site] ([3H]CGP61594 is a photoaffinity ligand), [3H]CGS19755 [glutamate site], [3H]CPP [glutamate site], [3H]glycine [glycine site], [3H]L689560 [glycine site], [3H]MDL105519 [glycine site], [3H]MK-801 [cation channel]

Nomenclature	GluN2D
HGNC, UniProt	GRIN2D, O15399
Endogenous agonists	D-aspartate [glutamate site] (GluN2D > GluN2C = GluN2B > GluN2A), D-serine [glycine site] (GluN2D > GluN2C > GluN2B > GluN2A), glycine [glycine site] (GluN2D > GluN2C > GluN2B > GluN2A), L-aspartate [glutamate site] (GluN2D = GluN2B > GluN2C = GluN2A)
Agonists	homoquinolinic acid [glutamate site] (Full agonist, GluN2B ≥ GluN2A ≥ GluN2D > GluN2C; partial agonist at GluN2A and GluN2C), (RS)-(tetrazol-5-yl)glycine [glutamate site] (Full agonist, GluN2D > GluN2C = GluN2B > GluN2A), NMDA [glutamate site] (Full agonist, GluN2D > GluN2C > GluN2B > GluN2A)
Selective antagonists	5,7-dichlorokynurenic acid [glycine site], CGP37849 [glutamate site], CGS19755 [glutamate site], conantokin-G [glutamate site] (GluN2B > GluN2D = GluN2C = GluN2A), d-AP5 [glutamate site], d-CCPene [glutamate site] (GluN2A = GluN2B > GluN2C = GluN2D), GV196771A [glycine site], L689560 [glycine site], L701324 [glycine site], LY233053 [glutamate site], UBP141 [glutamate site] (GluN2D ≥ GluN2C > GluN2A ≥ GluN2B) 180
Channel Blockers	amantidine (GluN2C = GluN2D ≥ GluN2B ≥ GluN2A), ketamine, memantine (GluN2C ≥ GluN2D ≥ GluN2B > GluN2A), Mg2+ (GluN2A = GluN2B > GluN2C = GluN2D), MK-801, N1-dansyl-spermine (GluN2A = GluN2B >> GluN2C = GluN2D), phencyclidine
Radioligands	[3H]CGP39653 [glutamate site], [3H]CGP61594 [glycine site] ([3H]CGP61594 is a photoaffinity ligand), [3H]CGS19755 [glutamate site], [3H]CPP [glutamate site], [3H]glycine [glycine site], [3H]L689560 [glycine site], [3H]MDL105519 [glycine site], [3H]MK-801 [cation channel]

Nomenclature	α1*	α2*	α3*
HGNC, UniProt	CHRNA1, P02708	CHRNA2, Q15822	CHRNA3, P32297
Commonly used antagonists	(α1)2β1γδ and (α1)2β1δε: α-bungarotoxin > pancuronium > vecuronium > rocuronium > (+)-tubocurarine (IC50 = 43 - 82 nM)	α2β2: DHβE (KB = 0.9 μM), (+)-tubocurarine (KB = 1.4 μM); α2β4: DHβE (KB = 3.6 μM), (+)-tubocurarine (KB = 4.2 μM)	α3β2: DHβE (KB = 1.6 μM, IC50 = 2.0 μM), (+)-tubocurarine (KB = 2.4 μM); α3β4: DHβE (KB = 19 μM, IC50 = 26 μM), (+)-tubocurarine (KB = 2.2 μM)
Selective agonists	succinylcholine (Full agonist, selective for (α1)2β1γδ)	–	–
Selective antagonists	α-bungarotoxin, α-conotoxin GI, α-conotoxin MI, pancuronium, waglerin-1 (selective for (α1)2β1δε)	–	α-conotoxin AuIB (α3β4), α-conotoxin-GIC (α3β2), α-conotoxin MII (α3β2), α-conotoxin PnIA (α3β2), α-conotoxin TxIA (α3β2)
Selective channel blockers (IC50)	gallamine ((α1)2β1γδ and (α1)2β1δε) (∼1x10-6 M), mecamylamine ((α1)2β1δε) (∼1.5x10-6 M)	hexamethonium, mecamylamine	A-867744(α3β4) 227, hexamethonium (α3β2), hexamethonium (α3β4), NS1738(α3β4) 237, mecamylamine (α3β4) (3.9x10-7 M), mecamylamine (α3β2) (7.6x10-6 M)
Selective allosteric regulators	–	LY2087101(Positive) 206	–
Radioligands (Kd)	[125I]α-bungarotoxin, [3H]α-bungarotoxin	[3H]cytisine, [125I]epibatidine (α2β2) (1x10-11 – 2.1x10-11 M - Rat), [3H]epibatidine (α2β2) (1x10-11 – 2.1x10-11 M - Rat), [125I]epibatidine (α2β4) (4.2x10-11 M), [3H]epibatidine (α2β4) (4.2x10-11 M), [125I]epibatidine (α2β4) (8.4x10-11 – 8.7x10-11 M - Rat), [3H]epibatidine (α2β4) (8.4x10-11 – 8.7x10-11 M - Rat)	[3H]cytisine, [125I]epibatidine (α3β2) (7x10-12 M), [3H]epibatidine (α3β2) (7x10-12 M), [125I]epibatidine (α3β2) (1.4x10-11 – 3.4x10-11 M - Rat), [3H]epibatidine (α3β2) (1.4x10-11 – 3.4x10-11 M - Rat), [125I]epibatidine (α3β4) (2.3x10-10 M), [3H]epibatidine (α3β4) (2.3x10-10 M), [125I]epibatidine (α3β4) (2.9x10-10 – 3.04x10-10 M - Rat), [3H]epibatidine (α3β4) (2.9x10-10 – 3.04x10-10 M - Rat)
Functional characteristics	(α1)2βγδ: PCa/PNa = 0.16 - 0.2, Pf = 2.1 – 2.9%; (α1)2βδε: PCa/PNa = 0.65 – 1.38, Pf = 4.1 – 7.2%	α2β2: PCa/PNa ∼ 1.5	α3β2: PCa/PNa = 1.5; α3β4: PCa/PNa = 0.78 - 1.1, Pf = 2.7 – 4.6%

Nomenclature	α4*	α6*	α7*
HGNC, UniProt	CHRNA4, P43681	CHRNA6, Q15825	CHRNA7, P36544
Commonly used antagonists	α4β2: DHβE (KB = 0.1 μM; IC50 = 0.08 - 0.9 μM), (+)-tubocurarine (KB = 3.2 μM, IC50 = 34 μM); α4β4: DHβE (KB = 0.01 μM, IC50 = 0.19 – 1.2 μM), (+)-tubocurarine (KB = 0.2 μM, IC50 = 50 μM)	α6/α3β2β3 chimera: DHβE (IC50 = 1.1 μM)	(α7)5: DHβE (IC50 = 8 - 20 μM); (α7)5: (+)-tubocurarine (IC50 = 3.1 μM)
Selective agonists	TC-2403(Full agonist, α4β2) 232, TC-2559(Full agonist, α4β2) 211	–	4BP-TQS(Full agonist, 4BP-TQS is an allosteric agonist) 215, A-582941(Full agonist, (α7)5) 204, PHA-543613(Full agonist, (α7)5) 239, PHA-709829(Full agonist, (α7)5) 200, PNU-282987(Full agonist, (α7)5) 205, TC-5619(Full agonist, (α7)5) 219
Selective antagonists	–	α-conotoxin MII (α6β2*), α-conotoxin MII [H9A, L15A] (α6β2β3), α-conotoxin PIA (α6/α3β2β3 chimera)	α-bungarotoxin ((α7)5), α-conotoxin ArIB ((α7)5), α-conotoxin ImI ((α7)5), methyllycaconitine ((α7)5)
Selective channel blockers (IC50)	A-867744(α4β2) 227, NS1738(α4β2) 237, mecamylamine (α4β4) (3.3x10-7 – 4.9x10-6 M), mecamylamine (α4β2) (3.6x10-6 – 4.1x10-6 M), hexamethonium (α4β2) (6.8x10-6 – 2.9x10-5 M), hexamethonium (α4β4) (9.1x10-5 M)	mecamylamine (α6/α3β2β3 chimera) (1.1x10-5 M), hexamethonium (α6/α3β2β3 chimera) (9.1x10-5 M)	mecamylamine ((α7)5) (1.56x10-5 M)
Selective allosteric regulators	LY2087101(Positive, potentiates α4β2 and α4β4) 206, NS9283(Positive, α4β2 and α4β4) 225	–	A-867744(Positive, (α7)5:Type 2; also blocks α3β4 and α4β2) 227, JNJ1930942 (Positive, (α7)5:Type 1/2) 214, LY2087101(Positive, (α7)5:Type 1) 206, NS1738(Positive, (α7)5:Type 1; also blocks α3β4 and α4β2) 237, PNU-120596(Positive, (α7)5:Type 2) 221
Radioligands (Kd)	[125I]epibatidine (α4β2) (1x10-11 – 3.3x10-11 M), [3H]epibatidine (α4β2) (1x10-11 – 3.3x10-11 M), [3H]cytisine (α4β2) (1x10-10 M - Rat), [3H]cytisine (α4β4) (1x10-10 M), [125I]epibatidine (α4β4) (1.87x10-10 M), [3H]epibatidine (α4β4) (1.87x10-10 M), [125I]epibatidine (α4β2) (3x10-10 – 4.6x10-10 M - Rat), [3H]epibatidine (α4β2) (3x10-10 – 4.6x10-10 M - Rat), [3H]nicotine (α4β2) (4x10-10 M - Rat), [3H]cytisine (α4β2) (4.3x10-10 – 6.3x10-10 M), [125I]epibatidine (α4β4) (8.5x10-10 – 9.4x10-10 M - Rat), [3H]epibatidine (α4β4) (8.5x10-10 – 9.4x10-10 M - Rat)	[125I]α-conotoxin MII, [3H]epibatidine (native α6β4*) (3.5x10-11 M - Chicken)	[3H]epibatidine ((α7)5) (6x10-13 M), [3H]A-585539(native α7) (7x10-11 M) 202, [3H]AZ11637326((α7)5) (2.3x10-10 M) 216, [125I]α-bungarotoxin ((α7)5) (7x10-10 – 5x10-9 M), [3H]α-bungarotoxin ((α7)5) (7x10-10 – 5x10-9 M), [3H]methyllycaconitine (native α7*) (1.9x10-9 M - Rat)
Functional characteristics	α4β2: PCa/PNa = 1.65, Pf = 2.6 – 2.9%; α4β4: Pf = 1.5 – 3.0 %	–	PCa/PNa = 6.6-20, Pf = 8.8 - 11.4%

Nomenclature	α8 (avian)*	α9*
HGNC, UniProt	–	CHRNA9, Q9UGM1
Commonly used antagonists	(α8)5: α-bungarotoxin > atropine ≥ (+)-tubocurarine ≥ strychnine	(α9)5: α-bungarotoxin > methyllycaconitine > strychnine ∼ tropisetron > (+)-tubocurarine; α9α10: α-bungarotoxin > tropisetron = strychnine > (+)-tubocurarine
Selective antagonists (IC50)	–	α-bungarotoxin (α9α10), α-bungarotoxin ((α9)5), α-conotoxin RgIA (α9α10), muscarine (α9α10), muscarine ((α9)5), nicotine (α9α10), nicotine ((α9)5), strychnine (α9α10), strychnine ((α9)5)
Radioligands (Kd)	[3H]epibatidine ((α8)5) (2x10-10 M), [125I]α-bungarotoxin (native α8*) (5.5x10-9 M), [3H]α-bungarotoxin (native α8*) (5.5x10-9 M)	[125I]α-bungarotoxin, [3H]α-bungarotoxin, [3H]methyllycaconitine (α9α10) (7.5x10-9 M)
Functional characteristics	–	(α9)5: PCa/PNa = 9; α9α10: PCa/PNa = 9, Pf = 22%

Nomenclature	P2X1	P2X2	P2X3	P2X4	P2X5	P2X6	P2X7
HGNC, UniProt	P2RX1, P51575	P2RX2, Q9UBL9	P2RX3, P56373	P2RX4, Q99571	P2RX5, Q93086	P2RX6, O15547	P2RX7, Q99572
Agonists	αβ-meATP (Full agonist), BzATP (Full agonist), L-βγ-meATP (Full agonist)	–	αβ-meATP (Full agonist), BzATP (Full agonist)	–	–	–	–
Antagonists (IC50)	TNP-ATP (∼1.3x10-9 M) 277, Ip5I (∼3.2x10-9 M), NF023 (∼2x10-7 M), NF449 (∼5x10-7 M) 259	–	TNP-ATP (∼1.3x10-9 M) 277, AF353 (∼1x10-8 M) 253, A317491 (∼3.1x10-8 M) 256, RO3 (∼3.1x10-8 M) 251	–	–	–	decavanadate (pA2 = 7.4) 269, A804598 (∼1x10-8 M), brilliant blue G (∼1x10-8 M) 258, A839977 (∼2x10-8 M) 248,250,254, A740003 (∼4x10-8 M), A438079 (∼1.25x10-7 M) 248
Selective allosteric regulators	MRS 2219 (Positive) 255	–	–	ivermectin (Positive) (Rat) 262	–	–	AZ11645373 (Negative) 267,275, chelerythrine (Negative) 273, ivermectin (Positive) 271, KN62 (Negative) 252,273
Comment	–	–	–	–	–	–	Effects of the allosteric modulators at P2X7 receptors are species-dependent

Nomenclature	HGNC, UniProt	Endogenous agonists (EC50)	Selective antagonists (IC50)	Functional characteristics	Comment
ZAC	ZACN, Q401N2	Zn2+ (Selective) (5x10-4 M) 278	(+)-tubocurarine (6.3x10-6 M) 278	Outwardly rectifying current (both constitutive and evoked by Zn2+)	Although tabulated as an antagonist, it is possible that (+)-tubocurarine acts as a channel blocker