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Am J Physiol Cell Physiol 291: C83-C92, 2006. First published February 15, 2006; doi:10.1152/ajpcell.00579.2005
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Channel phosphorylation and modulation of L-type Ca2+ currents by cytosolic Mg2+ concentration

Min Wang and Joshua R. Berlin

Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

Submitted 18 November 2005 ; accepted in final form 5 February 2006

Previous studies have shown that inhibition of L-type Ca2+ current (ICa) by cytosolic free Mg2+ concentration ([Mg2+]i) is profoundly affected by activation of cAMP-dependent protein kinase pathways. To investigate the mechanism underlying this counterregulation of ICa, rat cardiac myocytes and tsA201 cells expressing L-type Ca2+ channels were whole cell voltage-clamped with patch pipettes in which [Mg2+] ([Mg2+]p) was buffered by citrate and ATP. In tsA201 cells expressing wild-type Ca2+ channels ({alpha}1C/beta2A/{alpha}2{delta}), increasing [Mg2+]p from 0.2 mM to 1.8 mM decreased peak ICa by 76 ± 4.5% (n = 7). Mg2+-dependent modulation of ICa was also observed in cells loaded with ATP-{gamma}-S. With 0.2 mM [Mg2+]p, manipulating phosphorylation conditions by pipette application of protein kinase A (PKA) or phosphatase 2A (PP2A) produced large changes in ICa amplitude; however, with 1.8 mM [Mg2+]p, these same manipulations had no significant effect on ICa. With mutant channels lacking principal PKA phosphorylation sites ({alpha}1C/S1928A/beta2A/S478A/S479A/{alpha}2{delta}), increasing [Mg2+]p had only small effects on ICa. However, when channel open probability was increased by {alpha}1C-subunit truncation ({alpha}1C{Delta}1905/beta2A/S478A/S479A/{alpha}2{delta}), increasing [Mg2+]p greatly reduced peak ICa. Correspondingly, in myocytes voltage-clamped with pipette PP2A to minimize channel phosphorylation, increasing [Mg2+]p produced a much larger reduction in ICa when channel opening was promoted with BAY K8644. These data suggest that, around its physiological concentration range, cytosolic Mg2+ modulates the extent to which channel phosphorylation regulates ICa. This modulation does not necessarily involve changes in channel phosphorylation per se, but more generally appears to depend on the kinetics of gating induced by channel phosphorylation.

voltage-gated Ca2+ channel; cardiac myocytes; human embryonic kidney cells; protein kinase A; protein phosphatase 2A


Address for reprint requests and other correspondence: J. R. Berlin, Dept. of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07101-1709 (e-mail: berlinjr{at}umdnj.edu)






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