Regulation of cardiac Ca2+ channel by extracellular Na+

Hyponatremia is a predictor of poor cardiovascular outcomes during acute myocardial infarction and in the setting of preexisting heart failure [1]. There are no definitive mechanisms as to how hyponatremia suppresses cardiac function. In this report we provide evidence for direct down-regulation of Ca2+ channel current in response to low serum Na+. In voltage-clamped rat ventricular myocytes or HEK 293 cells expressing the L-type Ca2+ channel, a 15 mM drop in extracellular Na+ suppressed the Ca2+ current by ∼15%; with maximal suppression of ∼30% when Na+ levels were reduced to 100 mM or less. The suppressive effects of low Na+ on ICa, in part, depended on the substituting monovalent species (Li+, Cs+, TEA+), but were independent of phosphorylation state of the channel and possible influx of Ca2+ on Na+/Ca2+ exchanger. Acidification sensitized the Ca2+ channel current to Na+ withdrawal. Collectively our data suggest that Na+ and H+ may interact with regulatory site(s) at the outer recesses of the Ca2+ channel pore thereby directly modulating the electro-diffusion of the permeating divalents (Ca2+, Ba2+).