Details

Autor(en) / Beteiligte

• Parks, Randi J.
• Ray, Gibanananda
• Bienvenu, Laura A.
• Rose, Robert A.
• Howlett, Susan E.

Titel

Sex differences in SR Ca2+ release in murine ventricular myocytes are regulated by the cAMP/PKA pathway

Ist Teil von

• Journal of molecular and cellular cardiology, 2014-10, Vol.75, p.162-173

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Previous studies have shown that ventricular myocytes from female rats have smaller contractions and Ca2+ transients than males. As cardiac contraction is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, we hypothesized that sex differences in cAMP contribute to differences in Ca2+ handling. Ca2+ transients (fura-2) and ionic currents were measured simultaneously (37°C, 2Hz) in ventricular myocytes from adult male and female C57BL/6 mice. Under basal conditions, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ stores, and L-type Ca2+ current did not differ between the sexes. However, female myocytes had smaller Ca2+ transients (26% smaller), Ca2+ sparks (6% smaller), and excitation–contraction coupling gain in comparison to males (23% smaller). Interestingly, basal levels of intracellular cAMP were lower in female myocytes (0.7±0.1 vs. 1.7±0.2fmol/μg protein; p<0.001). Importantly, PKA inhibition (2μM H-89) eliminated male–female differences in Ca2+ transients and gain, as well as Ca2+ spark amplitude. Western blots showed that PKA inhibition also reduced the ratio of phospho:total RyR2 in male hearts, but not in female hearts. Stimulation of cAMP production with 10μM forskolin abolished sex differences in cAMP levels, as well as differences in Ca2+ transients, sparks, and gain. To determine if the breakdown of cAMP differed between the sexes, phosphodiesterase (PDE) mRNA levels were measured. PDE3 expression was similar in males and females, but PDE4B expression was higher in female ventricles. The inhibition of cAMP breakdown by PDE4 (10μM rolipram) abolished differences in Ca2+ transients and gain. These findings suggest that female myocytes have lower levels of basal cAMP due, in part, to higher expression of PDE4B. Lower cAMP levels in females may attenuate PKA phosphorylation of Ca2+ handling proteins in females, and may limit positive inotropic responses to stimulation of the cAMP/PKA pathway in female hearts. •We examine sex differences in SR Ca2+ release in ventricular myocytes in a murine model.•Myocytes from females have smaller Ca2+ transients and Ca2+ sparks, and lower EC coupling gain.•Females have less cAMP in basal conditions and higher PDE4B expression.•PKA inhibition abolishes sex differences in SR Ca2+ release and EC coupling gain.•Lower basal cAMP levels in females could limit SR Ca2+ release in response to positive inotropes.