The A‐kinase anchoring protein 15 regulates feedback inhibition of the epithelial Na + channel

Protein kinase A anchoring proteins or AKAPs regulate the activity of many ion channels. Protein kinase A (PKA) is a well‐recognized target of AKAPs, with other kinases now emerging as additional targets. We examined the roles of epithelial‐expressed AKAPs in regulating the epithelial Na + channel (ENaC). Experiments used heterologous expression with AKAP15, AKAP‐KL, and AKAP79 in Xenopus oo‐cytes. Experiments were carried out under high and low Na + conditions, as Na + loading is known to affect the baseline activity of ENaC in a PKC‐dependent mechanism. ENaC activity was unaffected by AKAP79 and AKAP‐KL expression. However, oocytes coexpressing AKAP15 exhibited an 80% and 91% reduction in the amiloride‐sensitive, whole‐cell conductance in high and low Na + conditions, respectively. The reduced channel activity was unaffected by PKA activation or inhibition, indicating a PKA‐independent mechanism. Expression with a membrane‐targeting domain, mutant form of AKAP15 (AKAP15m) prevented the decrease of ENaC activity, but only under low Na + conditions. In high sodium conditions, coexpression with AKAP15m led to an increase of ENaC activity to levels similar to those observed under low Na + . These results indicate that membrane‐associated AKAP15 reduces ENaC activity whereas the cytoplasmically associated one may participate in the channel's feedback inhibition by intracellular Na + , a process known to involve PKC. This hypothesis was further confirmed in coexpression experiments, which demonstrated functional and physical interaction between AKAP15 and PKCα. We propose that AKAP15 regulates ENaC via a novel PKA‐indepen‐dent pathway.—Bengrine, A., Li, J., Awayda, M. S. The A‐kinase anchoring protein 15 regulates feedback inhibition of the epithelial Na + channel. FASEB J. 21, 1189–1201 (2007)