Mobilization of calcium from intracellular stores facilitates somatodendritic dopamine release

J Neurosci. 2009 May 20;29(20):6568-79. doi: 10.1523/JNEUROSCI.0181-09.2009.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Boron Compounds / pharmacology
  • Cadmium / pharmacology
  • Calcium / metabolism*
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling / physiology
  • Chelating Agents / pharmacology
  • Chromones / pharmacology
  • Dendrites / metabolism*
  • Dopamine / metabolism*
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Electric Stimulation
  • Electrochemical Techniques / methods
  • Endoplasmic Reticulum / metabolism
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Indoles / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Intracellular Fluid / metabolism*
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Neurons / cytology*
  • Neurons / ultrastructure
  • Patch-Clamp Techniques / methods
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Substantia Nigra / cytology
  • Tyrosine 3-Monooxygenase / metabolism


  • 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester
  • Boron Compounds
  • Calcium Channels, L-Type
  • Chelating Agents
  • Chromones
  • Enzyme Inhibitors
  • Indoles
  • Inositol 1,4,5-Trisphosphate Receptors
  • Receptors, Metabotropic Glutamate
  • Ryanodine Receptor Calcium Release Channel
  • metabotropic glutamate receptor type 1
  • Cadmium
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • Methoxyhydroxyphenylglycol
  • 2-aminoethoxydiphenyl borate
  • Tyrosine 3-Monooxygenase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium
  • 3,4-dihydroxyphenylglycol
  • Dopamine
  • cyclopiazonic acid