Adenosine stimulation of Na+ transport is mediated by an A1 receptor and a [Ca2+]i-dependent mechanism

John P. Hayslett, Lawrence J. Macala, Joan I. Smallwood, Leena Kalghatgi, Jose Gasalla-Herraiz, Carlos Isales

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Abstract

Studies were performed to determine the primary signal transduction mechanism that mediates adenosine stimulation of electrogenic sodium transport in renal epithelial cells. Experiments were performed on cultured amphibian A6 cells with an adenosine analogue that preferentially binds to the A1 receptor, cyclohexyladenosine (CHA). Sodium transport was assessed by the equivalent short circuit current (Ieq). CHA was found to stimulate Ieq via activation of an A1 receptor because (1) the threshold concentration was 1 nM compared to that of 10 μM for the specific A2 agonist CGS21680, (2) CHA inhibited vasopressin (AVP)-stimulated cAMP production by a pertussis toxin-sensitive mechanism, and (3) the action of CHA was inhibited by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). CHA increased intracellular Ca2+ ([Ca2+]i) and stimulated phosphoinositide turnover at concentrations that increased Ieq and in a time course that paralleled the increase in Ieq. Ion transport was stimulated by a Ca2+-dependent mechanism because the CHA induced increase in Ieq was inhibited by chelating [Ca2+]i with 5,5′dimethyl BAPTA in a dose-dependent manner, with a Ki of approximately 10 μM. The increase in Ieq was also dose-dependently inhibited by the specific PKC inhibitors dihydroxychlorpromazine and chelerythrine, and by trifluoperazine which inhibits PKC and calmodulin. Further studies indicated that CHA-stimulated Ieq was independent of cAMP generation because CHA did not induce an increase in cAMP accummulation parallel to the increase in Ieq in a dose-response analysis, and the adenylate cyclase inhibitor 2′,5′ dideoxy-adenosine (DDA) did not affect the CHA-induced increase in Ieq. These studies indicate, therefore, that adenosine stimulation of Ieq occurs, at least in part, through calcium-dependent signal transduction events and not through regulation of adenylate cyclase.

Original languageEnglish (US)
Pages (from-to)1576-1584
Number of pages9
JournalKidney International
Volume47
Issue number6
DOIs
StatePublished - Jun 1995
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Hayslett, J. P., Macala, L. J., Smallwood, J. I., Kalghatgi, L., Gasalla-Herraiz, J., & Isales, C. (1995). Adenosine stimulation of Na+ transport is mediated by an A1 receptor and a [Ca2+]i-dependent mechanism. Kidney International, 47(6), 1576-1584. https://doi.org/10.1038/ki.1995.221