Dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto rat striatal cholinergic interneurones
Article first published online: 5 AUG 2004
The Journal of Physiology
Volume 533, Issue 2, pages 479–492, June 2001
How to Cite
Momiyama, T. and Koga, E. (2001), Dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto rat striatal cholinergic interneurones. The Journal of Physiology, 533: 479–492. doi: 10.1111/j.1469-7793.2001.0479a.x
- Issue published online: 5 AUG 2004
- Article first published online: 5 AUG 2004
- (Received 14 August 2000; accepted after revision 26 January 2001)
The modulatory roles of dopamine (DA) in inhibitory transmission onto striatal large cholinergic interneurones were investigated in rat brain slices using patch-clamp recording.
Pharmacologically isolated GABAA receptor-mediated IPSCs were recorded by focal stimulation within the striatum. Bath application of DA reversibly suppressed the amplitude of evoked IPSCs in a concentration-dependent manner (IC50, 10.0 μm).
A D2-like receptor agonist, quinpirole (3–30 μm), also suppressed the IPSCs, whereas a D1-like receptor agonist, SKF 81297, did not affect IPSCs. Sulpiride, a D2-like receptor antagonist, blocked the DA-induced suppression of IPSCs (apparent dissociation constant (KB), 0.36 μm), while a D1-like receptor antagonist, SCH 23390 (10 μm), had no effect.
DA (30 μm) reduced the frequency of spontaneous miniature IPSCs (mIPSCs) without changing their amplitude distribution, suggesting that GABA release was inhibited, whereas the sensitivity of postsynaptic GABAA receptors was not affected. The effect of DA on the frequency of mIPSCs was diminished when extracellular Ca2+ was replaced by Mg2+ (5 mm), indicating that DA affected the Ca2+ entry into the presynaptic terminal.
An N-type Ca2+ channel selective blocker, ω-conotoxin GVIA (ω-CgTX, 3 μm), suppressed IPSCs by 65.4%, whereas a P/Q-type Ca2+ channel selective blocker, ω-agatoxin IVA (ω-Aga-IVA, 200 nm), suppressed IPSCs by 78.4%. Simultaneous application of both blockers suppressed IPSCs by 95.9%. Assuming a 3rd power relationship between Ca2+ concentration and transmitter release, the contribution of N-, P/Q- and other types of Ca2+ channels to presynaptic Ca2+ entry is estimated to be, respectively, 29.8, 40.0 and 34.5% at this synapse. After the application of ω-CgTX, DA (30 μm) no longer affected IPSCs. In contrast, ω-Aga-IVA did not alter the level of suppression by DA, suggesting that the action of DA was selective for N-type Ca2+ channels.
A G protein alkylating agent, N-ethylmaleimide (NEM), significantly reduced the DA-induced suppression of IPSCs.
These results suggest that presynaptic D2-like receptors are present on the terminals of GABAergic afferents to striatal cholinergic interneurones, and down-regulate GABA release by selectively blocking N-type Ca2+ channels through NEM-sensitive G proteins.