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  • Title: Ca2+ entry-independent effects of L-type Ca2+ channel modulators on Ca2+ sparks in ventricular myocytes.
    Author: Copello JA, Zima AV, Diaz-Sylvester PL, Fill M, Blatter LA.
    Journal: Am J Physiol Cell Physiol; 2007 Jun; 292(6):C2129-40. PubMed ID: 17314267.
    Abstract:
    During the cardiac action potential, Ca(2+) entry through dyhidropyridine receptor L-type Ca(2+) channels (DHPRs) activates ryanodine receptors (RyRs) Ca(2+)-release channels, resulting in massive Ca(2+) mobilization from the sarcoplasmic reticulum (SR). This global Ca(2+) release arises from spatiotemporal summation of many localized elementary Ca(2+)-release events, Ca(2+) sparks. We tested whether DHPRs modulate Ca(2+)sparks in a Ca(2+) entry-independent manner. Negative modulation by DHPR of RyRs via physical interactions is accepted in resting skeletal muscle but remains controversial in the heart. Ca(2+) sparks were studied in cat cardiac myocytes permeabilized with saponin or internally perfused via a patch pipette. Bathing and pipette solutions contained low Ca(2+) (100 nM). Under these conditions, Ca(2+) sparks were detected with a stable frequency of 3-5 sparks.s(-1).100 microm(-1). The DHPR blockers nifedipine, nimodipine, FS-2, and calciseptine decreased spark frequency, whereas the DHPR agonists Bay-K8644 and FPL-64176 increased it. None of these agents altered the spatiotemporal characteristics of Ca(2+) sparks. The DHPR modulators were also without effect on SR Ca(2+) load (caffeine-induced Ca(2+) transients) or sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity (Ca(2+) loading rates of isolated SR microsomes) and did not change cardiac RyR channel gating (planar lipid bilayer experiments). In summary, DHPR modulators affected spark frequency in the absence of DHPR-mediated Ca(2+) entry. This action could not be attributed to a direct action of DHPR modulators on SERCA or RyRs. Our results suggest that the activity of RyR Ca(2+)-release units in ventricular myocytes is modulated by Ca(2+) entry-independent conformational changes in neighboring DHPRs.
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