Differential regulation of inotropy and lusitropy in overexpressed Gsα myocytes through cAMP and Ca2+ channel pathways

Abstract

We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gsα myocytes. Although baseline contractile function (percent contraction) in Gsα mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca 2+ transients, and Ca 2+ channel currents (I ca ) were greater in Gsα mice in response to 10 -8 M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca 2+ transients was accelerated at baseline in Gsα but did not increase further with ISO. In vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gsα mice. Forskolin and CaCl 2 increased contraction similarly in WT and Gsα mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca 2+ currents to ISO in WT and to forskolin in both WT and Gsα. It also blocked the accelerated relaxation in Gsα at baseline but not the contractile response to ISO in Gsα myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsα compared with WT. These data indicate that overexpression of Gsα accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca 2+ channel activity; i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMPdependent pathway.

Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility

“…Similarly, the receptor-mediated increase in Ca 2ϩ transient also did not cause any alteration in the diastolic Ca 2ϩ , the maximal rates of rise or decline, the time to 50% peak, or the time to 50% decline of the fluorescence ratio. The lack of any effect on the rates of shortening and relaxation of CS or those of Ca 2ϩ transient is consistent with an absence of an increase in cAMP level since cAMP is known to accelerate the rate of rise and relaxation with a shortening effect on the duration of both contraction and Ca 2ϩ transients (11,27). The P2X receptormediated increase in Ca 2ϩ transient was not due to any change in the action potential duration or characteristics since 2-meSATP had no effect on the APD 50 , APD 90 , or the resting membrane potential of the Tg cardiac myocyte.…”

β-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic Gsα mouse

“…One of the unique features of the overexpressed G sα model is the impact of the chronicity of the enhanced β-AR signaling. When the animals are examined as young adults, only enhanced LV function is observed (9)(10)(11), as occurs in other models of augmented β-AR signaling (2,3). However, when the animals reach 9-10 months of age, the cardiomyopathic process has begun, and is in full force by 14-18 months of age.…”

Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy

“…Cardiac myocytes were isolated as described previously (43). Longitudinal length of ventricular cardiac myocytes was determined as described (43). Whole cell currents were recorded using patch-clamp techniques (44).…”