Two intracellular pathways mediate metabotropic glutamate receptor-induced Ca2+ mobilization in dopamine neurons

Hitoshi Morikawa, Kamran Khodakhah, John T. Williams

Research output: Contribution to journalArticlepeer-review

137 Scopus citations


Activation of metabotropic glutamate receptors (mGluRs) causes membrane hyperpolarization in midbrain dopamine neurons. This hyperpolarization results from the opening of Ca2+-sensitive K+ channels, which is mediated by the release of Ca2+ from intracellular stores. Neurotransmitter-induced mobilization of Ca2+ is generally ascribed to the action of inositol 1,4,5-triphosphate (IP3) in neurons. Here we show that the mGluR-mediated Ca2+ mobilization in dopamine neurons is caused by two intracellular second messengers: IP3 and cyclic ADP-ribose (cADPR). Focal activation of mGluRs, attained by synaptic release of glutamate or iontophoretic application of aspartate, induced a wave of Ca2+ that spread over a distance of ∼50 μm through dendrites and the soma. Simultaneous inhibition of both IP3- and cADPR-dependent pathways with heparin and 8-NH2-cADPR was required to block the mGluR-induced Ca2+ release, indicating a redundancy in the signaling mechanism. Activation of ryanodine receptors was suggested to mediate the cADPR-dependent pathway, because ruthenium red, an antagonist of ryanodine receptors, inhibited the mGluR response only when the cADPR-dependent pathway was isolated by blocking the IP3-dependent pathway with heparin. Finally, the mGluR-mediated hyperpolarization was shown to induce a transient pause in the spontaneous firing of dopamine neurons. These results demonstrate that an excitatory neurotransmitter glutamate uses multiple intracellular pathways to exert an inhibitory control on the excitability of dopamine neurons.

Original languageEnglish (US)
Pages (from-to)149-157
Number of pages9
JournalJournal of Neuroscience
Issue number1
StatePublished - Jan 1 2003


  • Cyclic ADP-ribose
  • Dopamine neurons
  • Firing pattern
  • Inositol 1,4,5-triphosphate
  • Inositol 1,4,5-triphosphate receptors
  • Intracellular Ca signaling
  • Metabotropic glutamate receptors
  • Ryanodine receptors

ASJC Scopus subject areas

  • Neuroscience(all)


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