Inhibitory effect of calyculin a, serine/threonine protein
phosphatase type-i inhibitor, on renin secretion.
Park, Chun Sik, Mi Hyun Kim, Chae Hun Leem, Yeon Jin Jang, Hae Won
Kim, Hyoun Sik Kim, and Yoo Sun Hong.
Departments of Physiology, University of Ulsan, College of Medicine
and Asan Institute for Life Sciences, Seoul, Korea 138-736
APStracts 5:0135F, 1998.
We have recently showed that several putative selective inhibitors of
Ca2+-calmodulin dependent myosin light chain kinase (MLCK) such as
ML-9 reversibly stimulate renin secretion (Park et al. Am. J.
Physiol. 271, C242-C247, 1996). We hypothesized that Ca2+ inhibits
renin secretion via phosphorylation of 20-kDa myosin light chain
(MLC20) by activating MLCK. The present studies have investigated the
type of protein phosphatase(s)(PP) involved in the control of renin
secretion through inhibition of MLC dephosphorylation with the use of
inhibitors of various types of serine/threonine specific protein
phosphatases. Cyclosporin A, a putative inhibitor of PP type-2
(calcineurin), was without effects. Calyculin A and okadaic acid,
putative selective inhibitors of both the PP type-1(PP1) and
-2A(PP2A), significantly inhibited renin secretion under control
conditions. Calyculin A had at least 10-fold more potent inhibitory
effects than okadaic acid, suggesting PP1 rather than PP2A being
involved in the control of renin secretion. Furthermore, calyculin A
blocked the reversal of renin secretion preinhibited by raised
intracellular Ca2+ concentrations in a concentration dependent
manner. Calyculin A (10-6M) significantly inhibited renin secretion
stimulated by lowering intracellular Ca2+ concentrations, and blocked
stimulatory effect on renin secretion of ML-9. Taking all these
results together into considerations, we hypothesize that
dephosphorylation of MLC20 by Ca2+-independent PP1 stimulates renin
secretion whereas phosphorylation of MLC20 by Ca2+-calmodulin
dependent MLCK inhibits it. This hypothesized regulatory model of
renin secretion predicts that the rate of renin secretion at a given
time is determined by the ratio of the phosphorylated MLC20 to the
dephosphorylated MLC20 which is in turn determined by dynamic balance
between activity of the myosin light chain kinase and phosphatase.
Received 4 March 1998; accepted in final form 29 July 1998.
APS Manuscript Number F49-8.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 21 September 1998