Potassium Channelopathies and Gastrointestinal Ulceration.

Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.

INTRODUCTION

Potassium (K+) homeostasis involves the maintenance of the total body potassium content and plasma potassium levels at steady-state. It includes external K+ balance between dietary K+ intake and K+ excretion, and internal K+ balance between intracellular and extracellular compartments.1 Normally, people ingest about 100 mmol/day of K+ in their diets; they absorb about 90% of the K+ intake and excrete an equivalent amount of K+ (90 mmol/day) in the urine. Normal fecal K+ excretion averages about 10 mmol/day. More than 98% of potassium ions are intracellular, and only about 70 mmol (2%) are in the extracellular fluid. Factors that can alter potassium distribution between the intracellular and extracellular fluid are insulin, aldosterone, β-adrenergic stimulation, acidosis and alkalosis, cell lysis, and extracellular fluid osmolarity.2 Potassium constitutes the main intracellular electrolyte and osmolyte for fundamental processes such as membrane excitability, ion and solute transport or cell volume regulation. If intracellular and extracellular potassium levels are not properly maintained, it may lead to growth retardation, muscle weakness, and cardiac arrhythmia in a clinical setting. Potassium level is mainly regulated by the kidney. Both external and internal potassium homeostasis are largely maintained by potassium channels and transporters.3 They participate in the resting cellular-membrane potential and the propagation of action potential along with systemic blood-pressure control, vascular tone, gastrointestinal (GI) motility, glucose and insulin metabolism, mineralocorticoid action, acid-base balance, renal concentrating ability, and fluid and electrolyte balance.4 For example, an anomaly of a voltage-gated potassium channel can provoke congenital long QT syndrome, while a defect in the adenosine triphosphate (ATP)-sensitive potassium channel can provoke Bartter’s syndrome.5,6

Potassium channels represent the largest and most heterogeneous family of ion channels. In addition to trans-epithelial transport, various K+ channels are involved in cell volume regulation, differentiation, migration, apoptosis, and carcinogenesis.7 K+ channels consist of a primary pore-forming α-subunit often associated with regulatory β-subunits. In the human genome, there are more than 70 genes coding for α-subunit of K+ channels. Potassium channels are named by using the HUGO Gene Nomenclature Committee nomenclature.8 They are classified into four families: calcium-activated (Kca), inwardly rectifying (Kir), voltage-gated (Kv), and two-pore (K2p) K+ channels.

Transporters usually carry multiple ions at the same time while channels carry only a single ion. There are two P-type adenosine triphosphatases (ATPase) transporters: Na+/K+-ATPase and H+/K+-ATPase, along with an one of solute carrier (SLC) family: Na+/K+/2Cl− cotransporter (NKCC1).9

There has been a recent resurgence of interest in the area of GI motility, with reports that potassium channels in epithelial cells of the GI system also participate in external K+ balance. The function of these channels has not been well defined. Physiologically, potassium channels and transporters are involved in producing gastric acid and secreting in the stomach, and play roles in the absorptive and secretory pathways of potassium in the intestine. The function of K+ channels expressed in GI epithelial cells is described in Table 1. This commentary summarizes the available information of K+ channel expression and function in GI epithelial cells, and the relation of K+ channels to the mechanism of GI ulceration.

Table 1

Functional Expression of K+ Channels in Gastrointestinal Epithelial Cells

Channel	Name (HGNC)	Name (IUPHAR)	Other names	Oral	Esophagus	Stomach	Small intestine	Colon	Function/reference
Ca2+-activated K+ channel	KCNMA1	Kca1.1	BK, Slo, Maxi-K			+		+	Apical K+ secretion in distal colon47
									Increase in diarrhea/UC53,78
	KCNN4	Kca3.1	IK, SK4	+	+	+	+	+	Basolateral K+ absorption in stomach/intestine23,79
									Decrease in UC55
									Cell-protective role against osmotic change and anion secretion in stratified epithelia80
Inwardly rectifying K+ channel	KCNJ1	Kir1.1	ROMK	+		+			K+ recycling and regulate acid secretion22
									Maintaining taste buds cell hyperpolarization81
	KCNJ2	Kir2.1				+			K+ recycling in stomach19
	KCNJ8	Kir6.1	uKATP-1					+	Basolateral K+ absorption in colon44
	KCNJ10	Kir4.1				+			K+ recycling in stomach18
	KCNJ11	Kir6.2						+	Basolateral K+ absorption in colon44
	KCNJ13	Kir7.1				+			Coupled with Na+/K+-ATPase82
	KCNJ15	Kir4.2				+			K+ recycling in stomach21
Voltage-gated K+ channel	KCNA1	Kv1.1	RBK1			+	+		Regulation of cell migration and proliferation83,84
	KCNA4	Kv1.4					+	+	Cell migration inhibited by NSAIDs85
	KCNH2	Kv11.1	HERG			+		+	Increase in stomach/colon cancer86,87
	KCNQ1	Kv7.1	KvLQT1			+	+	+	Regulate acid secretion15
									Basolateral K+ absorption in intestine79

HGNC, HUGO Gene Nomenclature Committee; IUPHAR, International Union of Pharmacology; UC, ulcerative colitis; ATPase, adenosine triphosphatases; NSAIDs, nonsteroidal anti-inflammatory drugs.

K+ CHANNEL AND GASTRIC SECRETION

In the stomach mucosa, acid secretion occurs in a specialized cell type, the parietal cell. The acid producing enzyme H+/K+-ATPase (or proton pump) is an essential transporter involved in the final pathway of gastric acid secretion.10,11 This enzyme pumps H+ into the lumen in exchange for K+. In the resting state, proton pump is localized mainly in the cytoplasmic tubulovesicles below the plasma membrane. When gastric acid stimulants such as gastrin, histamine, or acetylcholine activate the parietal cell, the tubulovesicles move to and fuse with the apical secretory canaliculi, leading to expand the area of the canaliculi and increase gastric acid secretion.12 The half-life of gastric H+/K+-ATPase lasts for 50 hours, hence about 25% of pumps are synthesized per day.13

Gastric H+/K+-ATPase pump protons into the luminal space leading to more than one million-fold higher concentration of H+ in the gastric juice. Therefore, tubulovesicular K+ recycling pathway for K+ supply is required for avoiding K+ depletion of luminal fluid (Fig. 1). Although postulated for several years, it has a long time to determine the presence of such K+ recycling pathway in the gastric parietal cell. In KCNQ1 (Kv7.1) knockout mice, which has been related with “Long QT Syndrome Type I”, an unexpected stomach hyperplasia has been observed in 2000.14 Soon after the description of the gastric phenotype of KCNQ1 knockout mice, a couple of groups reported that the expression of KCNQ1 channel is abundantly expressed in human and mouse gastric mucosa.15,16

Fig. 1

Gastric acid secretion and K+ channels in a parietal cell of the stomach. Acid is produced from the hydration of CO2 to form H+ and HCO3−. Apical and tubulovesicular K+ channels provide K+ recycling, which is required for the function of the proton pump, H+/K+-ATPase.

There have been reliable evidences for a role of KCNQ1 in acid secretion of parietal cells, but not all H+/K+-ATPase-positive parietal cells show strong KCNQ1 expression. The exact localization and trafficking of these channels has remained obscure, and no evidence has been found for apical trafficking of these channels during acid secretion.17 Proton secretion was found to be suppressed by Barium, a nonspecific blocker of inwardly rectifying K+ channels. Localization and genomic studies have provided evidence for the presence of inward-rectifier K+ channels; KCNJ10 (Kir4.1) is localized at the apical microvilli of the parietal cell.18 Likewise KCNJ2 (Kir2.1) has been proposed as another luminal K+ channel in rabbit parietal cell.19 Trafficking of enhanced green fluorescent protein (EGFP)-tagged KCNJ10 (Kir4.1) channels in parietal cells shows KCNJ10 translocation to the apical secretory membrane after stimulation.20 KCNJ15 (Kir4.2) is also reported in H+/K+-ATPase-enriched tubulovesicles and translocation to the apical membrane.21 Recently ATP-sensitive KCNJ1 (Kir1.1; ROMK) colocalized with the β-subunit of H+/K+-ATPase in gastric parietal cells of wild-type mice, and Kir1.1-deficient mice show a defect in secretagogue-induced acid secretion in gastric glands.22 It has been shown that KCNN4 (Kca3.1) is expressed in the basolateral membrane of parietal cell.23

Inwardly rectifying K+ channels and KCNQ1 work together in potassium recycling across the apical pole of parietal cells. The statement that the correlation between K+ channels and gastric acid secretion by “No Potassium, No Acid” is open to question.24 However, the mechanisms of K+ dependent acid secretion in the stomach are still under investigation.

As shown in Fig. 1, concurrently with H+, Cl− extruded across the apical membrane via the different types of Cl− channels, the cystic fibrosis transmembrane regulator and SLC26A9, contribute to electroneutral net HCl secretion.25,26

Identification of the proton pump, H+/K+-ATPase, as the final step of gastric acid secretion provides an opportunity to develop a new class drug, a proton pump inhibitor (PPI). Omeprazole was discovered by a Swedish research group in 1981.27 Later on, lansoprazole, pantoprazole, and rabeprazole were subsequently developed. PPIs are widely used in the treatment of peptic ulcer disease and gastroesophageal reflux disease (GERD). They are weak-base prodrugs that accumulate and activate in the gastric parietal cell. Once activated within the parietal cell canaliculus, the PPI binds irreversibly with activated H+/K+-ATPase, resulting in the inhibition of gastric acid secretion.28 Thus the inhibition is long-lasting with no tolerance. However, they have a short plasma half-life of about 2 hours and bind only to activated H+/K+-ATPase, so it takes 4 to 5 days to achieve maximal acid suppression at therapeutic doses.29

On the contrary, the potassium-competitive acid blockers (P-CABs) reversibly inhibit acid secretion by competing with potassium on the luminal surface of the gastric H+/K+-ATPase.30 The first developed compound was SCH28080 in 1982.31 BY841, AZD0865, soraprazan (BY359), and several other P-CABs were subsequently developed. Animal and early clinical studies have demonstrated that P-CABs are highly selective for gastric H+/K+-ATPase and inhibit gastric acid secretion with fast onset of action.32 SCH28080 has been used extensively to explore the mechanism of inhibition of the proton pump.33,34 The first generation drugs were not released due to their brevity of action and hepatotoxicity.35 New P-CAB drugs, revaprazan (YH1885) and Vonoprazan (TAK-438) that overcome these shortcomings were recently launched.36,37 These drugs are highly selective and slower dissociation for gastric H+/K+-ATPase. Vonoprazan is not inferior to lansoprazole in the treatment of peptic ulcer disease and GERD, rather superior for eradication of Helicobacter pylori infection.

K+ CHANNEL IN COLONIC K+ HANDLING

Under normal circumstances, the kidneys maintain potassium homeostasis simply by matching excretion with dietary potassium intake, and the colon also plays a minor role in potassium excretion. The colon have the function of active potassium secretion and absorption. In patients with end-stage renal disease, colonic K+ secretion is believed to become a main determinant of K+ homeostasis. In extreme forms of secretory diarrhea like cholera, it is common to lose more than 5 L of water with a K+ loss of 100 to 200 mmol/day.38

One important aspect of K+ transport in the mammalian colon is in its segmental difference. Under normal conditions, the proximal colon shows net K+ secretion while the distal colon performs net K+ absorption.39 Active K+ absorption in the mammalian distal colon is conducted by nongastric H+/K+-ATPase (HKα2) in luminal membrane.40 The colonic H+/K+-ATPase (HKα2) is partially blocked by ouabain but not with omeprazole and SCH28080.41 For evaluation of the functional role of HKα2 in intestinal K+ handling, HKα2 knockout mice were used. On a normal diet, these mice sustain a normal K+ homeostasis even though they have a slightly increase of fecal K+ excretion. These mice do, however, develop profound hypokalemia on a K+-free diet.42 During K+ deprivation, colonic HKα2 plays a critical role in the maintenance of K+ homeostasis. KCNQ1 is located in basolateral membrane for active K+ absorption.43 Recently, ATP-sensitive inwardly rectifying K+ channels KCNJ8 (Kir6.1), KCNJ11 (Kir6.2) and regulatory sulfonylurea receptor subunits were discovered in rat distal colon.44

Net increase of K+ secretion is seen in animals with ingestion of high K+ diet both in the proximal colon and distal colon.45 It is assumed that Ca2+-activated K+ channels in colon are involved in K+ secretion.46 Convincing evidences from the study using the KCNMA1 (Kca1.1; large conductance; BK) α-subunit-deficient mouse show that this channel plays crucial role in K+ secretion in distal colon.47 It has been known that BK channels are responsible for resting and stimulated Ca2+-activated K+ secretion in mouse distal colon. BK channels has been variously referred to as the maxi-K or Slo channel. Another Ca2+-activated intermediate conductance K+ (IK) channel, referred as KCNN4 (Kca3.1) splice variants were identified in rat colon.48 KCNN4b and KCNN4c transcripts seems to encode basolateral and apical membrane proteins in distal colon, respectively. It is widely known aldosterone increases distal K+ secretion in colon, which is mediated by the BK channel and KCNN4c.49 Basolateral uptake of K+ via Na+/K+-ATPase and NKCC1 is required for active epithelial K+ secretion.50 These findings explain distal colonic K+ handling (Fig. 2). K+ channels which are related with K+ secretion in the proximal colon also needs to be investigated.51

Fig. 2

K+ absorption and secretion in an epithelial cell of the distal colon. K+ absorption is mediated by an apical colonic H+/K+-ATPase followed by basolateral K+ channels. K+ secretion is mediated by the basolateral Na+/K+-ATPase and Na+/K+/2Cl− cotransporter (NKCC1) followed by the efflux of apical K+ channels.

Many publications have shown that altered expression of BK channels maybe related with several conditions in intestinal disease. For example, in patients with severe diarrhea, large amounts of colonic K+ secretion frequently cause hypokalemia. In these cases, BK channels play a major role in controlling K+ secretion.52 Patients with severe ulcerative colitis (UC) often present hypokalemia. It has been reported the expression of BK channel is increased in patients with UC.53 In the dextran sulfate sodium (DSS)-induced colitis model, active K+ secretion was observed this is thought to relate to the up-regulation of the apical BK channel that is expressed three times more than control, whereas Cl− secretion is diminished.54 On the other hand, the basolateral IK channel expression and activity are markedly decreased in active UC.55 These studies suggests a strong correlation between potassium channel expression and pathogenesis of diarrhea in UC.

DRUG INFLUENCING K+ CHANNELS AND NOTABLE ULCERATION AS THEIR SIDE EFFECT

It is widely known over the last 20 years that high K+ intake increases the ATP-sensitive K+ channel (such as ROMK) expression and activity in the kidney.56 However, whether increased K+ channel activity causes ulceration in the GI tract is not clear. Several lines of evidence suggest that upregulation of the K+ channel may cause ulceration in the GI tract.

First, in the 1960s, the enteric coated potassium chloride tablet formulation was used in patients. During the use of this formulation, complicated cases were reported concerning the development of ulceration and perforation in the small intestine.57,58 K+ supplements are selectively being used for patients with hypokalemia, and GI ulceration is intermittently reported in these patients with the use of K+ supplements.59 From these cases, potassium ion itself proved to account for the development of a specific type of GI ulcer disease.

Second, it is presumed K+ channels are regulated by some of the nonsteroidal anti-inflammatory drugs (NSAIDs). It is well established that NSAIDs is a common cause of GI ulceration. It is generally agreed that inhibition of prostaglandin (PG) synthesis by cyclooxygenase (COX) is the principal mode of the analgesic and anti-inflammatory actions. NSAIDs-induced mucosal injury mechanism has been described as impaired mucosal defense from decreased mucoprotective PG production.60 In addition, arachidonic acid metabolism is shifted to the alternative 5-lipoxygenase pathway which increases synthesis of leukotrienes by nonselective NSAIDs,61 and enhances the production of proinflammatory mediators such as tumor necrosis factor α (TNF-α).62 Another mechanism of GI ulceration has been suggested, which is that NSAIDs have a direct cytotoxic effect on mucosal cell causing injury and damage.63 From one of these mechanism, a report shows that NSAIDs stimulate K+ efflux and increase the permeability of cell membrane.64 Some of these NSAIDs have been also identified as openers of ATP-sensitive K+ (K+ATP) channels, members of the Kir family, which participate in the antinociception in both the central and the peripheral nervous system.65 Meanwhile Celecoxib, a selective inhibitor of COX-2, has been known to have no effect on mucoprotective PG synthesis. In recently reported research, Celecoxib can modulate several ion channels and alter functioning of neurons and myocytes at clinically relevant concentrations independent of COX inhibition.66 This drug inhibits many voltage-gated ion channels including KCNQ1 (Kv7.1) that are regulatory channels of gastric acid secretion. However, whether NSAIDs and/or inhibition of PG regulate K+ channel expression and function in the GI system needs to be studied. A possible hypothesis to explain this side effect would be that the changes in the potassium channel in GI epithelial cells increase membrane permeability, which induces mucosal barrier defects and initiates ulceration.

Third, Nicorandil (2-nicotinamidoethyl-nitrate ester), which has been used clinically for as treatment for ischemic heart disease, possesses both nitrate-like and K+ATP channel activating properties.67 The nitric oxide (NO)-like action leads to dilatation of the large coronary arteries, whereas the potassium channel opening leads to the peripheral vasodilator and reduces both preload and afterload. This NO plays a beneficial role in mucosal defense by modulating the mucosal circulation in the stomach.68 Headache has been a main adverse event associated with the use of nicorandil. The side effects of oral and anal ulceration have been intermittently reported,69,70 which involve ulcerations throughout the GI tract.71,72 Peristomal and vulvar ulcerations are also described.73,74 The chance of this rare but potentially severe side effect increases with higher doses and long term use of this drug, and heals after drug withdrawal. A recent population-based study of this drug’s association with GI ulceration or perforation has been reported.75 This study, based on more than 600,000 randomly selected patients, found a 43% increase in the risk of GI ulceration and a 60% increase in the risk of GI perforation. Therefore, patient history should be taken at the time of diagnosis of GI ulceration to determine whether the patient is taking nicorandil and/or NSAIDs.

There is, however, a conflicting report about K+ATP channel. Diazoxide, which is known to be a K+ATP channel opener, has been used to control hypertension. Interestingly, nicorandil and diazoxide are effective in healing of acute gastric injury in an animal model.76,77

All this information elaborates that altered potassium channel and development of ulceration in GI tract are closely related. In-depth research of potassium channels in GI tract will help to illustrate the common pathway in molecular mechanism of ulceration.

CONCLUSIONS

Several potassium channels and transporters have been known to play roles in gastric acid production and secretion in terms of “No potassium, No acid.” Medications used for peptic ulcer disease often inhibit transporters of potassium. Potassium channels in small and large intestines have been studied to determine how they handle external K+ balance. Interestingly, increased expression of the BK potassium channel and decreased expression of the IK potassium channel expression have been observed in active UC in humans. Increased expression of BK channel have also been found in a rodent model of DSS-induced colitis. The drug, which has an action similar to the ATP-sensitive potassium channel openers such as Nicorandil and some NSAIDs, increases the incidence of GI ulceration. Longer duration of the use of high-dose Nicorandil increases the chance of developing oral and anal ulcerations, GI ulceration, and perforation of the GI tract. To conclude, the high correlation between potassium channels and development of ulceration suggests the presence of a novel mechanism of GI ulceration which indicates a common pathway of all types of ulceration developing throughout the GI tract. Further study on potassium channels in the GI epithelial cells offers significant insight into a mechanism of GI ulceration and development of potential drug candidate.