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Colonic Potassium Absorption and Secretion in Health and Disease

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ABSTRACT

The colon has large capacities for K+ absorption and K+ secretion, but its role in maintaining K+ homeostasis is often overlooked. For many years, passive diffusion and/or solvent drag were thought to be the primary mechanisms for K+ absorption in human and animal colon. However, it is now clear that apical H+,K+‐ATPase, in coordination with basolateral K+‐Cl cotransport and/or K+ and Cl channels operating in parallel, mediate electroneutral K+ absorption in animal colon. We now know that K+ absorption in rat colon reflects ouabain‐sensitive and ouabain‐insensitive apical H+,K+‐ATPase activities. Ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPases are localized in surface and crypt cells, respectively. Colonic H+,K+‐ATPase consists of α‐ (HKCα) and β‐ (HKCβ) subunits which, when coexpressed, exhibit ouabain‐insensitive H+,K+‐ATPase activity in HEK293 cells, while HKCα coexpressed with the gastric β‐subunit exhibits ouabain‐sensitive H+,K+‐ATPase activity in Xenopus oocytes. Aldosterone enhances apical H+,K+‐ATPase activity, HKCα specific mRNA and protein expression, and K+ absorption. Active K+ secretion, on the other hand, is mediated by apical K+ channels operating in a coordinated way with the basolateral Na+‐K+‐2Cl cotransporter. Both Ca2+‐activated intermediate conductance K+ (IK) and large conductance K+ (BK) channels are located in the apical membrane of colonic epithelia. IK channel‐mediated K+ efflux provides the driving force for Cl secretion, while BK channels mediate active (e.g., cAMP‐activated) K+ secretion. BK channel expression and activity are increased in patients with end‐stage renal disease and ulcerative colitis. This review summarizes the role of apical H+,K+‐ATPase in K+ absorption, and apical BK channel function in K+ secretion in health and disease. © 2018 American Physiological Society. Compr Physiol 8:1513‐1536, 2018.

Figure 1. Figure 1. Role of normal human small intestine and colon in K+ absorption and K+ secretion. Normal dietary K+ intake is approximately 90 mEq/day. Salivary, gastric, pancreatic, and intestinal secretions also contribute to the intestinal K+ content. Thus, approximately 83 mEq K+/day (i.e., 90%) is absorbed in the small intestine, and only 10 mEq K+/day (i.e., ∼10%) enters the colon. The colon secretes and absorbs 5 mEq K+/day, and thus fecal K+ excretion is 10 mEq/day. Small intestinal K+ absorption occurs secondary to passive driving forces, such as solvent drag and/or membrane electrical potential. Proximal colon secretes K+, while K+ absorption occurs in distal colon. Average lumen‐negative electrical potentials are −1, −8, −12, and −31 mV in the jejunum, ileum, proximal colon, and distal colon, respectively (). Outward and inward arrows indicate K+ absorption and K+ secretion, respectively. Thickness of arrows represent relative rate of absorption and secretion.
Figure 2. Figure 2. Cellular models of electroneutral K+ absorption in animal (guinea pig, mouse, and rat) distal colon. Apical H+,K+‐ATPase, and either basolateral parallel exit of K+ and Cl through respective channels (A) or K+‐Cl cotransport (KCC) (B), mediate electroneutral K+ absorption in animal colon. H+,K+‐ATPase‐mediated K+ absorption is partially Cl‐dependent. It is not known whether anion exchanger (AE)‐mediated Cl‐HCO3 exchange plays a role in Cl‐dependent K+ absorption.
Figure 3. Figure 3. Distribution of ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase along the surface to crypt cell axis in rat distal colon. Ouabain‐insensitive H+,K+‐ATPase is localized in surface cells and upper one‐third of matured crypt cells (yellow‐colored cells), while ouabain‐insensitive H+,K+‐ATPase is localized mainly to crypt cells (red‐colored cells). Vanadate (VO4, H+,K+‐ATPase inhibitor) inhibits both ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase.
Figure 4. Figure 4. Effect of Na+‐free diet (aldosterone) on active K+ absorption and active K+ secretion in rat colon. Active K+ secretion and active K+ absorption are present in proximal (lined segment) and distal segments of normal rat colon, respectively. Active K+ absorption is mediated by H+,K+‐ATPase, while active K+ secretion is mediated via large conductance K+ (BK) channels. Dietary Na+ depletion induces active K+ secretion in distal colon. Dietary Na+ depletion also stimulates H+,K+‐ATPase‐mediated active K+ absorption in distal colon. Dietary Na+ depletion enhances BK channel and H+,K+‐ATPase‐specific protein expression in distal colon. It is not known whether dietary Na+ depletion also stimulates active K+ secretion in proximal colon.
Figure 5. Figure 5. Cellular model of active K+ secretion. Coordinated activation of apical large conductance K+ (BK) channels, and basolateral Na+‐K+‐2Cl cotransporter (NKCC) and Cl channel 2 (ClC2) regulates active K+ secretion. K+ entering cells via basolateral NKCC (K+ loader) exits via apical BK channels. K+ entering via Na+,K+‐ATPase also contributes to apical BK channel‐mediated K+ secretion. Continuous K+ secretion depends on CLC2 and Na+,K+‐ATPase maintaining low intracellular levels of Cl and Na+, respectively. cAMP activates both basolateral NKCC and apical BK channel. Mucosal iberiotoxin IbTX inhibits active K+ secretion. [Reproduced, with permission, from ().]
Figure 6. Figure 6. Colonic epithelial cell models for basolateral membrane K+ channel‐regulated transport processes. (A) Under basal conditions, K+ recycling across basolateral membranes via intermediate conductance K+ (IK) channels operating in concert with Na+,K+‐ATPase, contributes to the favorable electrochemical gradient (reflecting high intracellular K+ and low intracellular Na+ concentrations, and a negative membrane potential) necessary for the secondary Na+ absorption mediated by apical Na+‐H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption. (B) Under stimulated condition (e.g., cholera), apical Cl exit via CFTR (cystic fibrosis transmembrane regulator) Cl channels following Na+‐K+‐2Cl (NKCC) transporter‐mediated basolateral Cl uptake tends to depolarize cells. This is counter‐balanced by the hyperpolarizing effect of K+ exit through basolateral IK channels, thus maintaining the electrical gradient required for sustained Cl secretion.
Figure 7. Figure 7. Effect of cellular cAMP increased by serosal addition of forskolin (FSK, adenylate cyclase activator) on K+ fluxes in the presence and absence of mucosal VO4 (P‐type ATPase inhibitor) in rat distal colon. (A) In the absence of mucosal VO4, FSK significantly inhibits active K+ absorption (i.e., net K+ absorption) by stimulating s‐m K+ fluxes. (B) Presence of 1 mmol/L mucosal VO4 unmasks FKS‐induced active K+ secretion. It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Fig. 11). Mucosal to serosal (m‐s) and serosal to mucosal (s‐m) 86Rb+ fluxes (K+ surrogate) were measured under voltage clamp condition in the absence (green bars) and presence (red bars) of forskolin. Net K+ fluxes were calculated by subtracting s‐m fluxes from m‐s fluxes. Positive and negative fluxes represent active K+ absorption and active K+ secretion, respectively. *P < 0.001—compared to respective fluxes in the absence of FSK; £P < 0.05—compared to in the absence of FSK. [Reproduced, with permission, from ref. ().]
Figure 8. Figure 8. Immunogold labeling of intermediate conductance K+ (IK) channels in colonic surface epithelial cells of normal rat distal colon (RtDC) and normal human colon (HuC). Cryosemithin sections were prepared and trypan blue‐stained for orientation (left column of each panel). Tissue specimens were ultratrimmed for cryothin sectioning, focusing on small areas of interest in the colonic surface epithelium to characterize plasma membrane domain‐specific localization of IK channel proteins at the ultrastructural level. Cryothin sections were immunolabeled with anti‐IKabc and detected with a secondary donkey anti‐rabbit 10 nm gold‐labeled antibody. Anti‐IKabc localized IK‐like proteins in apical [A], and lateral [L] plasma membrane domains of rat and human colonic epithelial cells, but not in basal plasma membranes [B] of surface epithelial enterocytes. These results using high‐resolution immunogold electron microscopy confirm our earlier results using confocal microscopy. [S] Surface epithelium; [C] crypts; [n] nucleus; [bm] basal plasma membrane. Images were acquired either at 400× primary magnification (cryosemithin section, bar = 20 µm) by light microscopy, or at 21,000× primary magnification (cryothin sections, bar = 200 nm) by electron microscopy. Similar results were obtained with two and three different human and rat tissues, respectively. [Reproduced, with permission, from ref. ().]
Figure 9. Figure 9. Indirect immunofluorescence imaging of intermediate conductance K+ (IK) channel protein in cRNA‐injected Xenopus oocytes. Anti‐IKabc antibody localized IK channel proteins to the plasma membrane of IKb cRNA‐injected oocytes (IKb), but not water injected (control) oocytes. IK protein was identified only in the cytoplasm, but not in the plasm membrane of IKc cRNA‐injected oocytes (IKc). Plasma membrane targeting of IK protein was substantially enhanced in oocytes coinjected with IKc and the BKβ1 subunit (i.e., large conductance K+ channel β‐subunit) cRNAs (IKc + BKβ1). Arrowheads indicate the absence (or minimal presence) of IK cahnnel proteins (left panels), while arrows indicate the presence of IK channel proteins (right panels) on the plasma membrane of oocytes. Fluorescence images were acquired using Nikon light microscope. Bar = 0.1 mm. [Adapted, with permission, from ref. ().]
Figure 10. Figure 10. Mucosal DC‐EBIO [intermediate conductance K+ (IK) channel opener] activates IK channel mediated K+ secretion in normal rat distal colon. Minimal K+ secretion is present under basal conditions. Mucosal DC‐EBIO stimulates active K+ secretion. Mucosal TRAM‐34 (IK channel blocker) inhibits DC‐EBIO‐stimulated K+ secretion. DC‐EBIO‐stimulated K+ secretion is not inhibited by mucosal iberiotoxin IbTX, large conductance K+ (BK) channel blocker). [Reproduced, with permission, from ref. ().]
Figure 11. Figure 11. Active K+ transport in normal and aldosterone‐treated (dietary Na+ depleted) rat distal colon. Net K+ transport was determined from the difference between mucosal to serosal (m‐s) and serosal to mucosal (s‐m) unidirectional fluxes measured under voltage clamp conditions. Net positive value represent active K+ absorption, while net negative value represent active K+ secretion. (A) Active K+ absorption present in normal rat distal colon (green bars) was inhibited by mucosal vanadate (VO4; P‐type ATPase inhibitor; red bars). (B) Active K+ secretion in aldosterone‐treated rat distal colon was further stimulated by mucosal VO4. *P < 0.001—compared to control; £P < 0.001—compared to control; P < 0.001—compared to control. [Reproduced, with permission, from ref. ().]
Figure 12. Figure 12. Effect of actinomycin D on aldosterone‐induced Isc in normal rat distal colon in vitro. (A) Normal rat distal colonic mucosal layers were mounted under voltage clamp condition in Ussing chambers. Immediately after mounting, either aldosterone (aldo) or aldosterone plus actinomycin D (transcriptional inhibitor) (aldo/act‐D) was added to the serosal bath. Short circuit current (Isc) was measured for up to 9 h. At the end of 8½ h, 10 µmol/L amiloride was added to mucosal bath. Enhanced Isc and inhbition of Isc by amiloride indicates that aldosterone induced epithelial Na+ channel (ENaC)‐mediated Na+ absorption (aldo). Absence of amiloride‐sensitive Isc in the presence of actinomycin D (aldo/act‐D) indicates that aldosterone‐induced ENaC‐mediated Na+ absorption is regulated at transcriptional level. (B) RT‐qPCR analyses indicated that aldosterone enhanced the abundance of large conductance K+ channel α‐subunit (BKα)‐specific mRNA (aldo), while this change was prevented by actinomycin D (aldo/act‐D). (C) K+ fluxes measured under voltage clamp condition indicate that aldosterone stimulated active K+ secretion (aldo), whereas this response was blocked by actinomycin D (aldo/act‐D). [Reproduced, with permission, from ref. ().]
Figure 13. Figure 13. Dextran sulfate sodium (DSS)‐induced inflammation stimulates active K+ secretion and abolishes agonist (cAMP and Ca2+)‐stimulated Cl secretion in rat distal colon. (A) Positive Isc (short circuit current) represents the presence of anion (Cl/HCO3) secretion under basal conditions. Increasing intracellular cAMP by forskolin (FSK; adenylate cyclase activator) stimulated active Cl secretion. Increasing intracellular Ca2+ by carbachol (CCH; adrenergic agonist; FSK/CCH) further transiently stimulated active Cl secretion. (B) Negative Isc indicates induced cation secretion and absence of anion secretion under basal conditions in DSS‐inflamed colon. The minimal increase in Isc induced by FSK, and the absence of a FSK/CCH‐induced Isc, indicated that Cl secretory processes were abolished in DSS‐inflamed colon. (C) In the presence of mucosal ortho‐VO4 (H+,K+‐ATPase inhibitor), minimal K+ absorption was present in normal colon (control). In normal colon, FSK stimulated active K+ secretion, while FSK/CCH had no additional effect on K+ secretion. (D) In DSS‐inflamed colon (control), active K+ secretion was present under basal conditions, but neither FSK nor FSK/CCH stimulated active K+ secretion. [Reproduced, with permission, from ref. ().]


Figure 1. Role of normal human small intestine and colon in K+ absorption and K+ secretion. Normal dietary K+ intake is approximately 90 mEq/day. Salivary, gastric, pancreatic, and intestinal secretions also contribute to the intestinal K+ content. Thus, approximately 83 mEq K+/day (i.e., 90%) is absorbed in the small intestine, and only 10 mEq K+/day (i.e., ∼10%) enters the colon. The colon secretes and absorbs 5 mEq K+/day, and thus fecal K+ excretion is 10 mEq/day. Small intestinal K+ absorption occurs secondary to passive driving forces, such as solvent drag and/or membrane electrical potential. Proximal colon secretes K+, while K+ absorption occurs in distal colon. Average lumen‐negative electrical potentials are −1, −8, −12, and −31 mV in the jejunum, ileum, proximal colon, and distal colon, respectively (). Outward and inward arrows indicate K+ absorption and K+ secretion, respectively. Thickness of arrows represent relative rate of absorption and secretion.


Figure 2. Cellular models of electroneutral K+ absorption in animal (guinea pig, mouse, and rat) distal colon. Apical H+,K+‐ATPase, and either basolateral parallel exit of K+ and Cl through respective channels (A) or K+‐Cl cotransport (KCC) (B), mediate electroneutral K+ absorption in animal colon. H+,K+‐ATPase‐mediated K+ absorption is partially Cl‐dependent. It is not known whether anion exchanger (AE)‐mediated Cl‐HCO3 exchange plays a role in Cl‐dependent K+ absorption.


Figure 3. Distribution of ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase along the surface to crypt cell axis in rat distal colon. Ouabain‐insensitive H+,K+‐ATPase is localized in surface cells and upper one‐third of matured crypt cells (yellow‐colored cells), while ouabain‐insensitive H+,K+‐ATPase is localized mainly to crypt cells (red‐colored cells). Vanadate (VO4, H+,K+‐ATPase inhibitor) inhibits both ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase.


Figure 4. Effect of Na+‐free diet (aldosterone) on active K+ absorption and active K+ secretion in rat colon. Active K+ secretion and active K+ absorption are present in proximal (lined segment) and distal segments of normal rat colon, respectively. Active K+ absorption is mediated by H+,K+‐ATPase, while active K+ secretion is mediated via large conductance K+ (BK) channels. Dietary Na+ depletion induces active K+ secretion in distal colon. Dietary Na+ depletion also stimulates H+,K+‐ATPase‐mediated active K+ absorption in distal colon. Dietary Na+ depletion enhances BK channel and H+,K+‐ATPase‐specific protein expression in distal colon. It is not known whether dietary Na+ depletion also stimulates active K+ secretion in proximal colon.


Figure 5. Cellular model of active K+ secretion. Coordinated activation of apical large conductance K+ (BK) channels, and basolateral Na+‐K+‐2Cl cotransporter (NKCC) and Cl channel 2 (ClC2) regulates active K+ secretion. K+ entering cells via basolateral NKCC (K+ loader) exits via apical BK channels. K+ entering via Na+,K+‐ATPase also contributes to apical BK channel‐mediated K+ secretion. Continuous K+ secretion depends on CLC2 and Na+,K+‐ATPase maintaining low intracellular levels of Cl and Na+, respectively. cAMP activates both basolateral NKCC and apical BK channel. Mucosal iberiotoxin IbTX inhibits active K+ secretion. [Reproduced, with permission, from ().]


Figure 6. Colonic epithelial cell models for basolateral membrane K+ channel‐regulated transport processes. (A) Under basal conditions, K+ recycling across basolateral membranes via intermediate conductance K+ (IK) channels operating in concert with Na+,K+‐ATPase, contributes to the favorable electrochemical gradient (reflecting high intracellular K+ and low intracellular Na+ concentrations, and a negative membrane potential) necessary for the secondary Na+ absorption mediated by apical Na+‐H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption. (B) Under stimulated condition (e.g., cholera), apical Cl exit via CFTR (cystic fibrosis transmembrane regulator) Cl channels following Na+‐K+‐2Cl (NKCC) transporter‐mediated basolateral Cl uptake tends to depolarize cells. This is counter‐balanced by the hyperpolarizing effect of K+ exit through basolateral IK channels, thus maintaining the electrical gradient required for sustained Cl secretion.


Figure 7. Effect of cellular cAMP increased by serosal addition of forskolin (FSK, adenylate cyclase activator) on K+ fluxes in the presence and absence of mucosal VO4 (P‐type ATPase inhibitor) in rat distal colon. (A) In the absence of mucosal VO4, FSK significantly inhibits active K+ absorption (i.e., net K+ absorption) by stimulating s‐m K+ fluxes. (B) Presence of 1 mmol/L mucosal VO4 unmasks FKS‐induced active K+ secretion. It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Fig. 11). Mucosal to serosal (m‐s) and serosal to mucosal (s‐m) 86Rb+ fluxes (K+ surrogate) were measured under voltage clamp condition in the absence (green bars) and presence (red bars) of forskolin. Net K+ fluxes were calculated by subtracting s‐m fluxes from m‐s fluxes. Positive and negative fluxes represent active K+ absorption and active K+ secretion, respectively. *P < 0.001—compared to respective fluxes in the absence of FSK; £P < 0.05—compared to in the absence of FSK. [Reproduced, with permission, from ref. ().]


Figure 8. Immunogold labeling of intermediate conductance K+ (IK) channels in colonic surface epithelial cells of normal rat distal colon (RtDC) and normal human colon (HuC). Cryosemithin sections were prepared and trypan blue‐stained for orientation (left column of each panel). Tissue specimens were ultratrimmed for cryothin sectioning, focusing on small areas of interest in the colonic surface epithelium to characterize plasma membrane domain‐specific localization of IK channel proteins at the ultrastructural level. Cryothin sections were immunolabeled with anti‐IKabc and detected with a secondary donkey anti‐rabbit 10 nm gold‐labeled antibody. Anti‐IKabc localized IK‐like proteins in apical [A], and lateral [L] plasma membrane domains of rat and human colonic epithelial cells, but not in basal plasma membranes [B] of surface epithelial enterocytes. These results using high‐resolution immunogold electron microscopy confirm our earlier results using confocal microscopy. [S] Surface epithelium; [C] crypts; [n] nucleus; [bm] basal plasma membrane. Images were acquired either at 400× primary magnification (cryosemithin section, bar = 20 µm) by light microscopy, or at 21,000× primary magnification (cryothin sections, bar = 200 nm) by electron microscopy. Similar results were obtained with two and three different human and rat tissues, respectively. [Reproduced, with permission, from ref. ().]


Figure 9. Indirect immunofluorescence imaging of intermediate conductance K+ (IK) channel protein in cRNA‐injected Xenopus oocytes. Anti‐IKabc antibody localized IK channel proteins to the plasma membrane of IKb cRNA‐injected oocytes (IKb), but not water injected (control) oocytes. IK protein was identified only in the cytoplasm, but not in the plasm membrane of IKc cRNA‐injected oocytes (IKc). Plasma membrane targeting of IK protein was substantially enhanced in oocytes coinjected with IKc and the BKβ1 subunit (i.e., large conductance K+ channel β‐subunit) cRNAs (IKc + BKβ1). Arrowheads indicate the absence (or minimal presence) of IK cahnnel proteins (left panels), while arrows indicate the presence of IK channel proteins (right panels) on the plasma membrane of oocytes. Fluorescence images were acquired using Nikon light microscope. Bar = 0.1 mm. [Adapted, with permission, from ref. ().]


Figure 10. Mucosal DC‐EBIO [intermediate conductance K+ (IK) channel opener] activates IK channel mediated K+ secretion in normal rat distal colon. Minimal K+ secretion is present under basal conditions. Mucosal DC‐EBIO stimulates active K+ secretion. Mucosal TRAM‐34 (IK channel blocker) inhibits DC‐EBIO‐stimulated K+ secretion. DC‐EBIO‐stimulated K+ secretion is not inhibited by mucosal iberiotoxin IbTX, large conductance K+ (BK) channel blocker). [Reproduced, with permission, from ref. ().]


Figure 11. Active K+ transport in normal and aldosterone‐treated (dietary Na+ depleted) rat distal colon. Net K+ transport was determined from the difference between mucosal to serosal (m‐s) and serosal to mucosal (s‐m) unidirectional fluxes measured under voltage clamp conditions. Net positive value represent active K+ absorption, while net negative value represent active K+ secretion. (A) Active K+ absorption present in normal rat distal colon (green bars) was inhibited by mucosal vanadate (VO4; P‐type ATPase inhibitor; red bars). (B) Active K+ secretion in aldosterone‐treated rat distal colon was further stimulated by mucosal VO4. *P < 0.001—compared to control; £P < 0.001—compared to control; P < 0.001—compared to control. [Reproduced, with permission, from ref. ().]


Figure 12. Effect of actinomycin D on aldosterone‐induced Isc in normal rat distal colon in vitro. (A) Normal rat distal colonic mucosal layers were mounted under voltage clamp condition in Ussing chambers. Immediately after mounting, either aldosterone (aldo) or aldosterone plus actinomycin D (transcriptional inhibitor) (aldo/act‐D) was added to the serosal bath. Short circuit current (Isc) was measured for up to 9 h. At the end of 8½ h, 10 µmol/L amiloride was added to mucosal bath. Enhanced Isc and inhbition of Isc by amiloride indicates that aldosterone induced epithelial Na+ channel (ENaC)‐mediated Na+ absorption (aldo). Absence of amiloride‐sensitive Isc in the presence of actinomycin D (aldo/act‐D) indicates that aldosterone‐induced ENaC‐mediated Na+ absorption is regulated at transcriptional level. (B) RT‐qPCR analyses indicated that aldosterone enhanced the abundance of large conductance K+ channel α‐subunit (BKα)‐specific mRNA (aldo), while this change was prevented by actinomycin D (aldo/act‐D). (C) K+ fluxes measured under voltage clamp condition indicate that aldosterone stimulated active K+ secretion (aldo), whereas this response was blocked by actinomycin D (aldo/act‐D). [Reproduced, with permission, from ref. ().]


Figure 13. Dextran sulfate sodium (DSS)‐induced inflammation stimulates active K+ secretion and abolishes agonist (cAMP and Ca2+)‐stimulated Cl secretion in rat distal colon. (A) Positive Isc (short circuit current) represents the presence of anion (Cl/HCO3) secretion under basal conditions. Increasing intracellular cAMP by forskolin (FSK; adenylate cyclase activator) stimulated active Cl secretion. Increasing intracellular Ca2+ by carbachol (CCH; adrenergic agonist; FSK/CCH) further transiently stimulated active Cl secretion. (B) Negative Isc indicates induced cation secretion and absence of anion secretion under basal conditions in DSS‐inflamed colon. The minimal increase in Isc induced by FSK, and the absence of a FSK/CCH‐induced Isc, indicated that Cl secretory processes were abolished in DSS‐inflamed colon. (C) In the presence of mucosal ortho‐VO4 (H+,K+‐ATPase inhibitor), minimal K+ absorption was present in normal colon (control). In normal colon, FSK stimulated active K+ secretion, while FSK/CCH had no additional effect on K+ secretion. (D) In DSS‐inflamed colon (control), active K+ secretion was present under basal conditions, but neither FSK nor FSK/CCH stimulated active K+ secretion. [Reproduced, with permission, from ref. ().]
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Further Reading

A comprehensive review of animal colonic H+,K+-ATPase was published by Binder et al (20), while reviews on human and animal colonic K+ channels were published by Sandle and Hunter (153), and Sorensen et al (175), respectively.

Barmeyer C, Rahner C, Yang Y, Sigworth FJ, Binder HJ, and Rajendran VM. Cloning and identification of tissue-specific expression of KCNN4 splice variants in rat colon. Am J Physiol Cell Physiol 299: C251-263, 2010.

Binder HJ, Sangan P, and Rajendran VM. Physiological and molecular studies of colonic H+,K+-ATPase. Semin Nephrol 19: 405-414, 1999.

Del Castillo JR, Rajendran VM, and Binder HJ. Apical membrane localization of ouabain-sensitive K(+)-activated ATPase activities in rat distal colon. Am J Physiol 261: G1005-1011, 1991.

Kanthesh BM, Sandle GI, and Rajendran VM. Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). Am J Physiol Cell Physiol 305: C972-980, 2013.

Singh SK, O'Hara B, Talukder JR, and Rajendran VM. Aldosterone induces active K(+) secretion by enhancing mucosal expression of Kcnn4c and Kcnma1 channels in rat distal colon. Am J Physiol Cell Physiol 302: C1353-1360, 2012.

 

 

Teaching Material

V. M. Rajendran, G. I. Sandle. Colonic Potassium Absorption and Secretion in Health and Disease. Compr Physiol 8: 2018, 1513-1536.

Didactic Synopsis

Major Teaching Points:

The gastrointestinal (GI) tract has enormous capacity to absorb and secrete K+ to maintain K+ homeostasis.

  1. K+ absorption:
    1. In vivo perfusion studies to evaluate unidirectional K+ fluxes showed passive K+ absorption is mediated by solvent drag in both animal and human colon.
    2. In vitro ion fluxes measured under voltage clamp condition, and biochemical and molecular studies of enzyme activities, identified apical H+,K+-ATPase as the mediator of active K+ absorption in animal colon.
    3. Aldosterone-stimulated active K+ absorption in animal colon reflects enhanced apical H+,K+-ATPase mRNA expression and protein activity.
    4. Although apical H+,K+-ATPase mediates active K+ absorption in animal colon, the molecular basis for K+ absorption in human colon has yet to be identified.
  2. K+ secretion:
    1. Active K+ secretion occurs in both animal and human colon.
    2. Apical K+ channels and basolateral Na+-K+-2Cl- cotransport coordinate active K+ secretion.
    3. Ca2+-activated large conductance K+ (BK) channels constitute the main apical K+ conductance for K+ exit into the lumen.
  3. Role and regulation of active K+ secretion:
    1. Aldosterone and high-K+ diet stimulate apical BK channel expression and active K+ secretion.
    2. Upregulated BK channel expression is the adaptive mechanism for K+ secretion in patients with end-stage renal disease.
    3. Increased BK channel expression and K+ secretion likely contribute to diarrhea in patients with ulcerative colitis.
    4. Potassium channels could be a potential therapeutic target to control diarrhea in ulcerative colitis.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Small intestine has a large capacity for K+ absorption. Humans normally consume 90 mEq K+/day. Small intestine is presented with dietary K+, and K+ within salivary, gastric, biliary, pancreatic and intestinal secretions. Since only 10 mEq K+/day passes from the small intestine into the colon, small intestine absorbs about 90 mEq K+/day. The colon (large intestine) is presented with K+ from the small intestine and that arising from colonic K+ secretion. The colon secretes 5 mEq K+/day and absorbs 5 mEq K+/day. As a result, 10 mEq K+/day is excreted in the feces. No active K+ absorptive mechanism has been identified in human small intestine, and thus K+ absorption may occur by solvent drag and/or be driven by membrane potential.

Figure 2 Teaching points: H+,K+-ATPase localized to the apical membranes has been shown to mediate active K+ absorption in animal (guinea pig, mouse, and rat) colon. H+,K+-ATPase-mediated electroneutral K+ absorption is partially Cl- dependent, but it is not known whether an anion exchanger (AE) linking Cl- absorption to HCO3- secretion is involved in K+ absorption. K+ absorbed across apical membranes exits across basolateral membranes via either K+ and Cl- channels operating in parallel, or K+-Cl- cotransport (KCC).

Figure 3 Teaching points: Active K+ absorption present in animal (guinea pig, mouse and rat) colon is partially inhibited by ouabain (Na+,K+-ATPase inhibitor), and therefore has both ouabain-sensitive and ouabain-insensitive components. Biochemical studies characterized ouabain-sensitive and ouabain-insensitive H+,K+-ATPase activities in animal colonic epithelial cells. Physiological studies monitoring the effect extracellular K+ on intracellular pH homeostasis in rat colon identified K+-dependent cellular pH homeostasis regulated by ouabain-sensitive and ouabain-insensitive H+,K+-ATPases localized to crypt cells (shown in red), and surface and upper third of crypt cells (shown in yellow), respectively. Both ouabain-sensitive and ouabain-insensitive H+,K+-ATPase are inhabited by vanadate (VO4, P-type ATPase inhibitor).

Figure 4 Teaching points: In rats, prolonged (7-10 days) feeding of a Na+-free diet increases circulating aldosterone levels. In rats fed a normal diet, large conductance K+ (BK) channels mediate active K+ secretion in the proximal colon, whereas H+,K+-ATPase mediates active K+ absorption in the distal colon (left panel). Aldosterone (induced by feeding a Na+-free diet) increases H+,K+-ATPase-mediated K+ absorption, and induces BK channel expression and BK channel-mediated K+ secretion in distal colon. It is not known whether aldosterone also stimulates BK channel-mediated K+ secretion in proximal colon.

Figure 5 Teaching points: Apical membrane K+ channels mediate active K+ secretion during pathological conditions of the colon, such as ulcerative colitis. Active K+ secretion requires the coordinated regulation of basolateral Na+-K+-2Cl- cotransporters (NKCC) and the Cl- channel-2 (CLC2), and apical BK channel. cAMP activates both NKCC and BK channels.

Figure 6 Teaching points: Under basal conditions, K+ exiting through basolateral K+ channels maintains Na+,K+-ATPase activity, thereby maintaining low intracellular Na+ and high intracellular K+ concentrations, and a negative intracellular electrical potential in colonic epithelial cells. This electrochemical gradient provides the driving force required for the secondary active Na+ absorption mediated by apical membrane Na+-H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption [A]. K+ exits through basolateral membrane intermediate conductance K+ (IK) channels, maintaining an intracellular K+ concentration that favors Na+-K+-2Cl- cotransporter (Cl- loader) function, which is required for continuous active Cl- secretion (e.g., during cholera infection) through apical membrane cystic fibrosis transmembrane regulator (CFTR) Cl- channels [B].

Figure 7 Teaching points: Increasing intracellular cAMP (by adding forskolin, FSK, an activator of adenylate cyclase) inhibits active (net) K+ absorption present under basal conditions in normal rat distal colon (A). Mucosal presence of vanadate (VO4; H+,K+-ATPase inhibitor) unmasks cAMP-stimulated K+ secretion (B). It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Figure-11). cAMP does not inhibit H+,K+-ATPase, but activates K+ channels and stimulates active K+ secretion. Inhibition of net K+ absorption by cAMP is secondary to the stimulation of active K+ secretion.

Figure 8 Teaching points: Intermediate conductance K+ (IK) channel-like proteins are localized to both the apical and lateral membranes of normal rat and human colon. K+ exiting through IK channels provides the driving force for active Cl- secretion during secretory diarrhea (e.g., cholera).

Figure 9 Teaching points: Apical membrane-specific intermediate conductance K+ (IKC) channels, which lack a transmembrane domain, requires a β-subunit-like accessory (“chaperon”) protein for plasma membrane expression in Xenopus oocytes. In the absence of “chaperon,” IKC proteins are expressed only in the cytoplasm.

Figure 10 Teaching points: K+ secretion following activation of apical membrane intermediate conductance K+ (IK) channels is inhibited by TRAM-34 (IK channel specific blocker). IK channel-mediated K+ secretion is not inhabited by iberiotoxin (IbTX, BK channel specific blocker).

Figure 11 Teaching points: In normal rat distal colon, H+,K+-ATPase-mediated active K+ absorption is inhibited by mucosal VO4 (H+,K+-ATPase inhibitor). In aldosterone-treated rat distal colon, which exhibits active K+ secretion, inhibition of H+,K+-ATPase-mediated K+ absorption by VO4 further enhances K+ secretion.

Figure 12 Teaching points: Aldosterone induces large conductance K+ channel α subunit (BKα) specific mRNA abundance and active K+ secretion. The aldosterone-induced BKα abundance occurs at the transcription level.

Figure 13 Teaching points: cAMP and cAMP/Ca2+ stimulate both active Cl- and K+ secretion in normal colon. Inflammation abolishes both cAMP- and Ca2+-stimulated Cl- and K+ secretion, and also results in active K+ secretion.

 


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Vazhaikkurichi M. Rajendran, Geoffrey I. Sandle. Colonic Potassium Absorption and Secretion in Health and Disease. Compr Physiol 2018, 8: 1513-1536. doi: 10.1002/cphy.c170030