L-type calcium channel contribution to striatal dopamine release is governed by calbindin-D28K, the dopamine transporter, D2-receptors, α2δ-subunits and sex differences

Abstract

AbstractCa2+ entry to nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes to pacemaker activity and DA release, but burdens cells with a metabolic stress promoting their vulnerability to parkinsonian degeneration. The level of LTCC function varies between subtypes of DA neurons, but is not proportional to LTCC expression level, indicating that LTCC function is governed by other factors. We used fast-scan cyclic voltammetry in mouse brain slices to identify mechanisms that govern whether LTCCs contribute to DA release in dorsal and ventral striatum. We find that calbindin-D28K limits LTCC function in a regionally and sexually divergent manner; D2-receptors and DA transporters are negative and positive regulators respectively; and lastly, that targeting α2δ subunits with gabapentinoid drugs restricts LTCC function without compromising DA release. These data reveal that LTCC function in DA axons is dynamically and locally regulated, which may prove useful for future neuroprotective strategies.