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CARDIOVASCULAR |
1 Department of Physiology and Biophysics, University of Washington Box 357290, Seattle, WA 98195, USA
2 Children's Hospital Medical Center for Molecular Cardiovascular Biology, 3333 Burnet Avenue MLC7020, Cincinnati, OH 45229-3039, USA
In arterial smooth muscle, protein kinase C
(PKC) coerces discrete clusters of L-type Ca2+ channels to operate in a high open probability mode, resulting in subcellular domains of nearly continual Ca2+ influx called ‘persistent Ca2+ sparklets’. Our previous work suggested that steady-state Ca2+ entry into arterial myocytes, and thus global [Ca2+]i, is regulated by Ca2+ influx through clusters of L-type Ca2+ channels operating in this persistently active mode in addition to openings of solitary channels functioning in a low-activity mode. Here, we provide the first direct evidence supporting this ‘Ca2+ sparklet’ model of Ca2+ influx at a physiological membrane potential and external Ca2+ concentration. In support of this model, we found that persistent Ca2+ sparklets produced local and global elevations in [Ca2+]i. Membrane depolarization increased Ca2+ influx via low-activity and high-activity persistent Ca2+ sparklets. Our data indicate that Ca2+ entering arterial smooth muscle through persistent Ca2+ sparklets accounts for approximately 50% of the total dihydropyridine-sensitive (i.e. L-type Ca2+ channel) Ca2+ influx at a physiologically relevant membrane potential (–40 mV) and external Ca2+ concentration (2 mM). Consistent with this, inhibition of basal PKC-dependent persistent Ca2+ sparklets decreased [Ca2+]i by about 50% in isolated arterial myocytes and intact pressurized arteries. Taken together, these data support the conclusion that in arterial smooth muscle steady-state Ca2+ entry and global [Ca2+]i are regulated by low-activity and PKC-dependent high-activity persistent Ca2+ sparklets.
(Received 6 November 2006;
accepted after revision 30 November 2006;
first published online 7 December 2006)
Corresponding author L. F. Santana: Department of Physiology and Biophysics, University of Washington Box 357290, Seattle, WA 98195, USA. Email: santana{at}u.washington.edu
This article has been cited by other articles:
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