Developmental and tissue-specific regulation of rabbit skeletal and cardiac muscle calcium channels involved in excitation-contraction coupling.

Abstract

Two types of calcium channels signal excitation-contraction (E-C) coupling in striated muscle: dihydropyridine receptors (DHPRs, voltage-gated L-type calcium channels on the transverse tubule) and ryanodine receptors (RyRs, calcium release channels on the sarcoplasmic reticulum). Sarcolemmal depolarization activates the DHPR; subsequently, the RyR is activated and releases calcium that activates muscle contraction. We show in the present study that expression of the E-C coupling calcium channels is upregulated during myogenic development in the rabbit. Skeletal and cardiac muscle isoforms of the following genes were examined: the DHPR alpha 1, alpha 2, beta, and gamma subunits and the RyR. Distinct cardiac and skeletal muscle-specific cDNAs were isolated, encoding each of the DHPR subunits and the RyR. The skeletal muscle DHPR alpha 1, alpha 2, beta, and gamma subunits and the cardiac DHPR alpha 1 subunit mRNA levels increased on the day of birth and at the adult stage compared with fetal levels. The skeletal and cardiac RyR mRNA levels increased on the day of birth and at adult stages compared with fetal levels. Ryanodine binding sites increased in both skeletal and cardiac muscle. We now provide a molecular explanation for the physiological "maturation" of the E-C coupling apparatus observed at the day of birth and during early postnatal development in both skeletal and cardiac muscles. Low levels of calcium channel expression in fetal cardiac and skeletal muscle make these tissues more sensitive to pharmacological therapy with calcium channel blockers, a phenomenon that has been reported in human neonates.

Regulation of calcium channel expression in neonatal myocytes by catecholamines.

“…rDHPR-C1 encodes the II-S6 region of the rat heart DHP receptor ␣ 1 subunit and is 92% identical to the published rabbit sequence. Northern hybridizations using heart DHP receptor ␣ 1 subunit cDNA probes typically identify three mRNAs in rabbit and mouse, ‫ف‬ 8, 9.5, and 22 kb (7,18,19). In the rabbit all three mRNAs are regulated coordinately during development (18).…”

Sorcin Associates with the Pore-forming Subunit of Voltage-dependent L-type Ca2+ Channels

“…None of these proteins were detected in undifferentiated C2C12 myoblasts (Fig. 1C, lane 1); up-regulation of the ␣ 1S subunit during skeletal muscle development has been established (45,46). The anti-sorcin antibody immunoprecipitated only the most slowly migrating form that was detected in myotubes, while lower M r forms that were reactive with SKN were not recovered (Fig.…”

Gene Expression of SERCA2a and L- and T-type Ca Channels during Human Heart Development

“…the ␣ 1C subunit increased by 2-3 fold between the perinatal period and adulthood (33). In contrast to rabbit, Ca current density in cultured rat neonatal myocytes is much greater than in acutely isolated rat adult myocytes (34).…”

“…Inhibition of this Ca influx would be expected to adversely affect the fetal heart. It has been suggested that during fetal and neonatal stages, when expression of L-type Ca channels involved in EC-coupling is low, small doses of Ca channel blockers could have adverse effects on the myocardium (33). A Ca channel blocking effect could result in diminished cardiac contractility.…”