Involvement of transient receptor potential‐like channels in responses to mGluR‐I activation in midbrain dopamine neurons

Abstract

We investigated the involvement of store-operated channels (SOCs) and transient receptor potential (TRP) channels in the response to activation of the group I metabotropic glutamate receptor subtype 1 (mGluR1) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG, puff application) in dopamine neurons in rat brain slices. The mGluR1-induced conductance reversed polarity close to 0 mV and at more positive potentials when extracellular potassium concentrations were increased, indicating the involvement of a cationic channel. DHPG currents but not intracellular calcium responses were reduced by low extracellular sodium concentrations but were not affected by sodium channel blockers, tetrodotoxin and saxitoxin or by inhibition of the h-current with cesium. Abolition of calcium responses with intracellular BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; 10 mm) did not affect current responses, indicating they were not calcium activated. Extracellular application of non-selective SOCs and TRP channel blockers 2-aminoethoxydiphenylborane (2-APB), SKF96365, ruthenium red and flufenamic acid (but not gadolinium) reduced DHPG current and calcium responses. Intracellular application of ruthenium red and 2-APB did not affect DHPG currents, indicating that IP3 and ryanodine receptors did not mediate their actions. Single-cell PCR revealed the presence of TRPC1 and 5 mRNA in most dopamine neurons and subtypes 3, 4 and 6 in some. Store depletion evoked calcium entry indicative of SOCs, providing the first functional observation of such channels in native central neurons. Store depletion with either cyclopiazonic acid or ryanodine abolished calcium but not current responses to DHPG. The electrophysiological and pharmacological properties of the mGluR1-induced inward current are consistent with the involvement of TRP channels whereas calcium responses are dependent on the function of SOCs in voltage clamp recordings.

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

“…This indicates that DAG is not the final messenger through which kisspeptin induces an inward current in GnRH neurons. It also indicates that heteromers within TRPC1, TRPC4, and TRPC5 subfamily or between the TRPC1, TRPC4, and TRPC5 subfamily and TRPC3, TRPC6, and TRPC7 subfamily might be formed and activated in GnRH neurons, which is consistent with the fact that the kisspeptinevoked currents are strongly inhibited by both 2-APB and FFA, but not potentiated by La 3ϩ (Tozzi et al, 2003;Trebak et al, 2003;Zagranichnaya et al, 2005).…”

“…Indeed, 2-APB (100 M), which is a potent blocker of TRPC3, TRPC4, TRPC5, and TRPC6 channels, and FFA, which is a potent blocker of TRPC3, TRPC5, and TRPC7, did inhibit the effects of kisspeptin in GnRH neurons. These blockers had a similar efficacy on the mGluR1 activation of TRPC channels in substantia nigra dopamine neurons (Tozzi et al, 2003) and basolateral amygdala (Faber et al, 2006), and on CCK2 activation of TRPC channels in amygdala neurons (Meis et al, 2007). Therefore, although all of the "brain" TRPC channels are expressed in GnRH neurons, the TRPC4 and TRPC5 appear to be key players in mediating the effects of kisspeptin in GnRH neurons based on the I-V relationship and the pharmacology (Lee et al, 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). In addition, recent studies have shown that the peptide cholecystokinin via its receptor (CCK2) can also activate what appears to be TRPC1, TRPC4, and TRPC5 channels in amygdala neurons (Meis et al, 2007).…”

Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5

“…The inward current is owing to a Trp conductance (Tozzi et al, 2003), and the outward current is mediated by SK channels (Fiorillo and Williams, 1998). Both the inward and outward currents were blocked by the combination of the NAMs (referred to subsequently as blockers) JNJ (500 nM) and MPEP (300 nM, Figure 2), which block mGluR1 and mGluR5, respectively.…”

Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: Potential implications for Rett syndrome

“…Recent evidence indicates that TRPC1-containing channels mediate cation currents activated by the selective group-I mGluR agonist DHPG in Purkinje neurons (Kim et al, 2003). Similar DHPG-evoked currents sensitive to TRPC inhibitors were also recorded in hippocampal pyramidal neurons (Gee et al, 2003;Rae and Irving, 2004), and midbrain dopamine neurons (Tozzi et al, 2003). In addition, membrane currents mediated by TRPC channels activated by group-I mGluRs in response to endogenously released glutamate have been observed in Purkinje cells (Kim et al, 2003), dopamine neurons of the substantia nigra compacta (Bengtson et al, 2004), and neurons in the lateral amygdala (Faber et al, 2006).…”