Calcium Handling Remodeling Underlies Impaired Sympathetic Stress Response in Ventricular Myocardium from Haploinsufficient Rats.

encodes the pore-forming α1C subunit of the L-type Ca channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of rats with a main focus on cellular Ca handling mechanisms. Under basal conditions, isolated ventricular myocytes exhibited unaltered L-type Ca current, Ca transients (CaTs), sarcoplasmic reticulum (SR) Ca load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca influx and fractional SR Ca release after treatment with isoprenaline were smaller in than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, myocytes display remodeling of Ca handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca influx, SR Ca release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in cardiomyocytes.