CACNA1Cencodes the pore-forming α1C subunit of the L-type Ca2+channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. HaploinsufficientCacna1c+/−rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype ofCacna1c+/−rats with a main focus on cellular Ca2+handling mechanisms. Under basal conditions, isolated ventricularCacna1c+/−myocytes exhibited unaltered L-type Ca2+current, Ca2+transients (CaTs), sarcoplasmic reticulum (SR) Ca2+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) inCacna1c+/−rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in bothCacna1c+/−and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired inCacna1c+/−myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca2+influx and fractional SR Ca2+release after treatment with isoprenaline were smaller inCacna1c+/−than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated inCacna1c+/−compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings,Cacna1c+/−myocytes display remodeling of Ca2+handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca2+influx, SR Ca2+release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 inCacna1c+/−cardiomyocytes.