Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon.

Zhang J, Halm ST, Halm DR. Role of the BK channel (K(Ca)1.1) during activation of electrogenic K+ secretion in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 303: G1322-G1334, 2012. First published October 11, 2012; doi: 10.1152/ajpgi.00325.2012.-Secretagogues acting at a variety of receptor types activate electrogenic K+ secretion in guinea pig distal colon, often accompanied by Cl- secretion. Distinct blockers of K(Ca)1.1 (BK, Kcnma1), iberiotoxin (IbTx), and paxilline inhibited the negative short-circuit current (I-sc) associated with K+ secretion. Mucosal addition of IbTx inhibited epinephrine-activated I-sc (I-epi(sc)) and transepithelial conductance ((epi)G(t)) consistent with K+ secretion occurring via apical membrane K(Ca)1.1. The concentration dependence of IbTx inhibition of I-epi(sc) yielded an IC50 of 193 nM, with a maximal inhibition of 51%. Similarly, IbTx inhibited (epi)G(t) with an IC50 of 220 nM and maximal inhibition of 48%. Mucosally added paxilline (10 mu M) inhibited I-epi(sc) and (epi)G(t) by similar to 50%. IbTx and paxilline also inhibited I-sc activated by mucosal ATP, supporting apical K(Ca)1.1 as a requirement for this K+ secretagogue. Responses to IbTx and paxilline indicated that a component of K+ secretion occurred during activation of Cl- secretion by prostaglandin-E-2 and cholinergic stimulation. Analysis of K(Ca)1.1 alpha mRNA expression in distal colonic epithelial cells indicated the presence of the ZERO splice variant and three splice variants for the COOH terminus. The presence of the regulatory beta-subunits K-Ca beta 1 and K-Ca beta 4 also was demonstrated. Immunolocalization supported the presence of K(Ca)1.1 alpha in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K+ secretion involving apical membrane K(Ca)1.1 during activation by several secretagogue types, but the observed K+ secretion likely required the activity of additional K+ channel types in the apical membrane.