Published online before print January 24, 2002, doi: 10.1161/hh0402.105666
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Submitted on August 16, 2001
Revised on January 14, 2002
Accepted on January 14, 2002
L-Type Ca2+ Currents Overlapping Threshold Na+ Currents. Could They Be Responsible for the "Slip-Mode" Phenomenon in Cardiac Myocytes?
Valentino Piacentino III ;
From the Cardiovascular Research Group, Molecular and Cellular Cardiology Laboratories, Temple University School of Medicine, Philadelphia, Pa.
* To whom correspondence should be addressed. E-mail: srhouser{at}unix.temple.edu.
Phosphorylation of Na channels has been suggested to increase their Ca permeability. Termed "Slip-Mode Conductance" (SMC), this hypothesis predicts that Ca influx via protein kinase A (PKA)--modified Na channels can induce sarcoplasmic reticulum (SR) Ca release. We tested this hypothesis by determining if SR Ca release is graded with INa in the presence of activated PKA (with Isoproterenol, ISO). Vm, Im, and [Ca]i were measured in feline (n=26) and failing human (n=19) ventricular myocytes. Voltage steps from -70 through -40 mV were used to grade INa. Na channel antagonists (tetrodotoxin), L-type Ca channel (ICa,L) antagonists (nifedipine, cadmium, Verapamil), and agonists (Bay K 8644, FPL 64176) were used to separate SMC from ICa,L. In the absence of ISO, INa was associated with SR Ca release in human but not feline myocytes. After ISO, graded INa was associated with small amounts of SR Ca release in feline myocytes and the magnitude of release increased in human myocytes. INa-related SR Ca release was insensitive to tetrodotoxin (n=10) but was blocked by nifedipine (n=10) and cadmium (n=3). SR Ca release was induced over the same voltage range in the absence of ISO with Bay K 8644 and FPL 64176 (n=9). Positive voltage steps (to 0 mV) to fully activate Na channels (SMC) in the presence of ISO and Verapamil only caused SR Ca release when block of ICa,L was incomplete. We conclude that PKA-mediated increases in ICa,L and SR Ca loading can reproduce many of the experimental features of SMC.
Key words: calcium current • excitation-contraction coupling • sarcoplasmic reticulum • sodium current
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