TrpC3/C7 and Slo2.1 Are Molecular Targets for Metabotropic Glutamate Receptor Signaling in Rat Striatal Cholinergic Interneurons

Abstract

Large aspiny cholinergic interneurons provide the sole source of striatal acetylcholine, a neurotransmitter critical for basal ganglia function; these tonically active interneurons receive excitatory inputs from corticostriatal glutamatergic afferents that act, in part, via metabotropic glutamate receptors (mGluRs). We combined electrophysiological recordings in brain slices with molecular neuroanatomy to identify distinct ion channel targets for mGluR1/5 receptors in striatal cholinergic interneurons: transient receptor potential channel 3/7 (TrpC3/C7) and Slo2.1. In recordings obtained with methanesulfonate-based internal solutions, we found an mGluR-activated current with voltage-dependent and pharmacological properties reminiscent of TrpC3 and TrpC7; expression of these TrpC subunits in cholinergic interneurons was verified by combined immunohistochemistry and in situ hybridization, and modulation of both TrpC channels was reconstituted in HEK293 (human embryonic kidney 293) cells cotransfected with mGluR1 or mGluR5. With a chloridebased internal solution, mGluR agonists did not activate interneuron TrpC-like currents. Instead, a time-dependent, outwardly rectifying K ϩ current developed after whole-cell access, and this Cl Ϫ -activated K ϩ current was strongly inhibited by volatile anesthetics and mGluR activation. This modulation was recapitulated in cells transfected with Slo2.1, a Na ϩ -and Cl Ϫ -activated K ϩ channel, and Slo2.1 expression was confirmed histochemically in striatal cholinergic interneurons. By using gramicidin perforated-patch recordings, we established that the predominant agonist-activated current was TrpC-like when ambient intracellular chloride was preserved, although a small K ϩ current contribution was observed in some cells. Together, our data indicate that mGluR1/5-mediated glutamatergic excitation of cholinergic interneurons is primarily a result of activation of TrpC3/TrpC7-like cationic channels; under conditions when intracellular NaCl is elevated, a Slo2.1 background K ϩ channel may also contribute.

Kisspeptin Depolarizes Gonadotropin-Releasing Hormone Neurons through Activation of TRPC-Like Cationic Channels

“…Error bars indicate SEM. channels consisting of the TRPC1, TRPC4, and TRPC5 subfamily Plant and Schaefer, 2003) as well as TRPC3, TRPC6, and TRPC7 subfamily (Trebak et al, 2003;Berg et al, 2007). Indeed, based on the scRT-PCR, we found that all of the transcripts were expressed in GnRH neurons with exception of TRPC2, which is not functionally expressed in the mammalian brain (Clapham, 2003).…”

“…In fact, in the CNS, TRPC channels are probably one of the major targets for mGluR1 signaling (Tozzi et al, 2003;Bengtson et al, 2004;Faber et al, 2006;Berg et al, 2007). Interestingly, in substantia nigra dopamine neurons, TRPC1 and TRPC5 are highly expressed and the mGluR1 agonist dihydroxyphenylglycine-induced current yields an "S" shape current-voltage plot (Tozzi et al, 2003).…”

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

“…In hippocampal neurons and pontine neurons, TRPC3 is reportedly activated through a pathway that is initiated by binding of brain-derived neurotrophic factor to TrkB, engagement of a PLC␥, and activation of the inositol trisphosphate receptor (Li et al, 1999;Amaral and Pozzo-Miller, 2007), whereas in striatal cholinergic neurons or cerebellar Purkinje neurons, mGluR1s activate TRPC3 (Berg et al, 2007;Hartmann et al, 2008). TRPC3 is also reportedly involved in brain-derived neurotrophic factor-induced axon guidance or neuronal survival in cerebellar granule cells Jia et al, 2007).…”

Activation of Metabotropic Glutamate Receptors Induces Periodic Burst Firing and Concomitant Cytosolic Ca2+Oscillations in Cerebellar Interneurons

“…Canonical transient receptor potential channels (TRPCs), first demonstrated to be present in brain tissue and susceptible to be activated by G q -coupled receptors by Strübing et al (2001), are attractive candidates to underlie the measured currents because they have been shown to link to group I mGluRs in neuronal cells (Gee et al, 2003;Bengtson et al, 2004;Berg et al, 2007;Ene et al, 2007;Wang et al, 2007) . Generally, the single-channel conductance of other TRP channels is larger than the value obtained for TRPC1, 3, and 4.…”