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Volume 272, Number 15, Issue of April 11, 1997 pp. 9902-9906
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Regulation of Large Calcium-activated Potassium Channels by Protein Phosphatase 2A

(Received for publication, December 23, 1996, and in revised form, January 28, 1997)

From the Division of Renal Diseases and Hypertension and the Department of Integrative Biology, Pharmacology, and Physiology, The University of Texas Medical School, Houston, Texas 77073

Vasodilating agents induce relaxation of mesangial cells, in part through cGMP-mediated activation of large calcium-activated potassium channels (BK_Ca). Normally quiescent in cell-attached patches, the response of BK_Ca to nitric oxide, atrial natriuretic peptide, and dibutyryl cGMP (Bt₂cGMP) is characterized by a biphasic increase and then decrease ("rundown") in open probability. Using the patch-clamp method in conjunction with phosphatase inhibitors, we investigated whether the run-down phase was the result of dephosphorylation by an endogenous protein phosphatase. In cell-attached patches, cantharidic acid (500 nM), okadaic acid (100 nM), and calyculin A (100 nM), nondiscriminant inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A) at these concentrations, caused a significantly greater and sustained response of BK_Ca to Bt₂cGMP. Within 2 min, the response of BK_Ca to the combination of cantharidic acid and Bt₂cGMP was greater than the response to these agents added separately. Incubation of mesangial cells with okadaic acid for 20 min at a concentration (5 nM) specific for PP2A increased the basal open probability of BK_Ca and completely inhibited rundown after activation by Bt₂cGMP. Incubation with calyculin A (10 nM), a more potent inhibitor of PP1, did not affect BK_Ca activity. In inside-out patches, Bt₂cGMP plus MgATP caused a sustained activation of BK_Ca that was inhibited by exogenous PP2A but not PP1. It is concluded that either BK_Ca or a tightly associated regulator of BK_Ca is a common substrate for endogenous cGMP-activated protein kinase, which activates BK_Ca, and PP2A, which inactivates BK_Ca, in human mesangial cells.

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