Apical membrane P2Y4 purinergic receptor controls K+ secretion by strial marginal cell epithelium

The transepithelial short circuit current (Isc) represents electrogenic K+ secretion and was found to be decreased by uridine 5'-triphosphate (UTP), adenosine 5'-triphosphate (ATP) and diadenosine tetraphosphate (Ap4A) but not uridine 5'-diphosphate (UDP) at the apical membrane of marginal cells of the gerbil stria vascularis. The potencies of these agonists were consistent with rodent P2Y4 and P2Y2 but not P2Y6 receptors. Activation caused a biphasic increase in intracellular [Ca2+] that could be partially blocked by 2-aminoethoxy-diphenyl borate (2-APB), an inhibitor of the IP3 receptor and store-operated channels. Suramin (100 μM) did not inhibit the effect of UTP (1 μM). The ineffectiveness of suramin at the concentration used was consistent with P2Y4 but not P2Y2. Transcripts for both P2Y2 and P2Y4 were found in the stria vascularis. Sustained exposure to ATP or UTP for 15 min caused a depression of Isc that appeared to have two components but with apparently no chronic desensitization.The results support the conclusion that regulation of K+ secretion across strial marginal cell epithelium occurs by P2Y4 receptors at the apical membrane. The apparent lack of desensitization of the response is consistent with two processes: a rapid-onset phosphorylation of KCNE1 channel subunit and a slower-onset of regulation by depletion of plasma membrane PIP2.A high concentration of K+ is maintained in the lumen of the cochlea via electrogenic secretion by the strial marginal cell epithelium [1]. One pathway of regulation is the coupling of purinergic receptors on the apical membrane of these cells to the apical potassium channels (IKs) which mediate secretion [2]. These receptors are responsive to both ATP and UTP as agonists and they were found to exert their action via the phospholipase C – protein kinase C intracellular signal pathway [3]. At the time of the original investigations, the purinergic receptor field recognized only 1 receptor responding to uracil nucleotides