Constitutive activity of the dopamine (D 5 ) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca V 3.2 and Ca V 3.3 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.
(© 2022 British Pharmacological Society.)