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 ([Ca(2+)](o)), suggesting the involvement of intracellular Ca(2+) stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) that sequesters cytosolic Ca(2+) into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activation by Ca(2+) 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 Ca(2+) stores in somatodendritic DA release. Implicating IP(3)R-dependent stores, an IP(3)R antagonist, 2-APB, also decreased evoked [DA](o). Moreover, DHPG, an agonist of group I metabotropic glutamate receptors (mGluR1s, which couple to IP(3) 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 IP(3)R-gated Ca(2+) stores. Similarly, activation of RyRs by caffeine increased [Ca(2+)](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 [Ca(2+)](o), suggesting a mechanism for maintenance of somatodendritic DA release with limited Ca(2+) entry. Thus, both mGluR1-linked IP(3)R- and RyR-dependent ER Ca(2+) stores facilitate somatodendritic DA release in the SNc.
Patel
Jyoti C
JC
Department of Neurosurgery, New York University School of Medicine, New York, New York 10016, USA.
Witkovsky
Paul
P
Avshalumov
Marat V
MV
Rice
Margaret E
ME
D000818:Animals; D001369:Axons / Q000378:metabolism*; D001896:Boron Compounds / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003712:Dendrites / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D055664:Electrochemical Techniques / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques / Q000379:methods; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D001896:Boron Compounds; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D007211:Indoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018094:Receptors, Metabotropic Glutamate; D019837:Ryanodine Receptor Calcium Release Channel; C104077:metabotropic glutamate receptor type 1; D002104:Cadmium; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D008734:Methoxyhydroxyphenylglycol; C109986:2-aminoethoxydiphenyl borate; D014446:Tyrosine 3-Monooxygenase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; C000543:cyclopiazonic acid