Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents

Background and Purpose Ca V 3.1‐3 currents differentially contribute to neuronal firing patterns. Ca V 3 are regulated by G protein‐coupled receptors (GPCRs) activity, but information about Ca V 3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D 5 recpetor constitutive activity, a GPCR with high levels of basal activity, on Ca V 3 functionality. D 5 recpetor and Ca V 3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach Our study models were HEK293T cells heterologously expressing D 1 or D 5 receptor and Ca V 3.1‐3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D 1 /D 5 inverse agonist) and a D 5 receptor mutant lacking constitutive activity as experimental tools. We measured Ca V 3 currents and excitability parameters using the patch‐clamp technique. We completed our study with computational modelling and imaging technique. Key Results We found a higher sensitivity to TTA‐P2 (Ca V 3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine‐treated animals compared with vehicle‐treated animals. We found that Ca V 3.2 and Ca V 3.3—but not Ca V 3.1—are targets of D 5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine‐treated animals in comparison with vehicle‐treated animals. Similar changes in firing rate were observed on a neuronal model with controlled Ca V 3 currents levels. Conclusions and Implications Native hippocampal Ca V 3 and recombinant Ca V 3.2‐3 are sensitive to D 5 receptor constitutive activity. Manipulation of D 5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.