Abstract
BackgroundIt was previously shown that K+ secretion by strial marginal cell epithelium is under the control of G-protein coupled receptors of the P2Y family in the apical membrane. Receptor activation by uracil nucleotides (P2Y2, P2Y4 or P2Y6) leads to a decrease in the electrogenic K+ secretion. The present study was conducted to determine the subtype of the functional purinergic receptor in gerbil stria vascularis, to test if receptor activation leads to elevation of intracellular [Ca2+] and to test if the response to these receptors undergoes desensitization.ResultsThe 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.ConclusionThe 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.
Highlights
It was previously shown that K+ secretion by strial marginal cell epithelium is under the control of G-protein coupled receptors of the P2Y family in the apical membrane
The known members of the mammalian metabotropic, G protein-coupled, purinergic receptors has since grown to P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14 [4]
adenosine 5'-triphosphate (ATP) perfused for 30 s at the apical side of strial marginal cell epithelium caused a monophasic decrease in Isc (Fig. 1A), consistent with previous findings [2]
Summary
It was previously shown that K+ secretion by strial marginal cell epithelium is under the control of G-protein coupled receptors of the P2Y family in the apical membrane. Receptor activation by uracil nucleotides (P2Y2, P2Y4 or P2Y6) leads to a decrease in the electrogenic K+ secretion. SgFiuingmaulmrcearll1ys recordings of Isc (Ussing chamber) of strial marSummary recordings of Isc (Ussing chamber) of strial marginal cells during apical perfusion of A) ATP (10-3 M; 30 s; n = 6), B) UTP (10-4 M; 30 s; n = 7) and C) Ap4A (3 × 10-4 M; 60 s; n = 4). 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]. The pharmacologic distinction between P2Y2 and P2Y4 was more ambiguous and the accepted criteria changed rapidly [7]
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