Aldosterone activates colonic K secretion via BK channels (KCa1.1) and membrane trafficking (1097.9)

Aldosterone (aldo) activates electrogenic K+ secretion in guinea pig distal colon via a mechanism requiring protein synthesis. Channel blocker sensitivity supported conductive apical K+ exit and basolateral Cl‐ exit during aldo stimulation, similar to adrenergic activation. Paxilline [1 μM], BK channel (KCa1.1, Kcnma1) blocker, inhibited ~50% of short‐circuit current (Isc) and transepithelial conductance (Gt) activated by aldo; and, CaCCinh‐A01 [30 μM], Ca++‐activated Cl‐ channel blocker, eliminated aldoIsc and decreased aldoGt. Signaling for K+ secretion by aldo involved cAMP and serum‐glucocorticoid protein kinase (sgk) as indicated by elimination of aldoIsc with inhibition of soluble adenylyl cyclase by KH7 [30 μM] or sgk by GSK‐650394 [10 μM]. Elimination of aldoIsc by inhibiting dynamin (dyngo‐4a [30 μM]) or clathrin (pitstop‐2 [20 μM]) indicated a requirement for clathrin dependent endocytosis during aldo signaling. Manipulating the ubiquitylation cycle by inhibiting ubiquitin‐E1 ligase (UBEI‐41 [50 μM]) also inhibited aldoIsc; and, disrupting membrane localization of small GTPases such as ras, rho, or rab with farnesyltiosalicylate [10 μM] abolished aldoIsc. Dependence on microtubular transport was supported by loss of aldoIsc with inhibiting dynein (ciliobrevin‐D [10 μM]). Together these results support an aldosterone signaling mechanism for activating electrogenic K+ secretion involving cAMP, sgk, endocytosis, and microtubular transport. [NIH DK65845]