Mobilization of Calcium from Intracellular Stores Facilitates Somatodendritic Dopamine Release

Somatodendritic dopamine (DA) release in the substantia nigra pars compacta (SNc) shows a limited dependence on extracellular calcium concentration ([Ca2+]o), suggesting the involvement of intracellular Ca2+ stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) that sequesters cytosolic Ca2+ into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activation by Ca2+ entry. Using fast-scan cyclic voltammetry to monitor evoked extracellular DA concentration ([DA]o) in midbrain slices, we found that SERCA inhibition by cyclopiazonic acid (CPA) decreased evoked [DA]o in the SNc, indicating a functional role for ER Ca2+ stores in somatodendritic DA release. Implicating IP3R-dependent stores, an IP3R antagonist, 2-APB, also decreased evoked [DA]o. Moreover, DHPG, an agonist of group I metabotropic glutamate receptors (mGluR1s, which couple to IP3 production), increased somatodendritic DA release, whereas CPCCOEt, an mGluR1 antagonist, suppressed it. Release suppression by mGluR1 blockade was prevented by 2-APB or CPA, indicating facilitation of DA release by endogenous glutamate acting via mGluR1s and IP3R-gated Ca2+ stores. Similarly, activation of RyRs by caffeine increased [Ca2+]i and elevated evoked [DA]o. The increase in DA release was prevented by a RyR blocker, dantrolene, and by CPA. Importantly, the efficacy of dantrolene was enhanced in low [Ca2+]o, suggesting a mechanism for maintenance of somatodendritic DA release with limited Ca2+ entry. Thus, both mGluR1-linked IP3R- and RyR-dependent ER Ca2+ stores facilitate somatodendritic DA release in the SNc.