Peptide hormone ghrelin enhances neuronalexcitability by inhibition of Kv7/KCNQ channels

摘要

The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantianigra pars compacta, where dopaminergic neurons modulate the function of thenigrostriatal system for motor coordination. Here we describe a novel mechanism by whichghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassiumKv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway.Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelininhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHSR1a,PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice orchannel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricularghrelin administration causes increased dopamine release and turnover in thestriatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results incontralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administrationof the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signalling is likely a common pathway utilized by the nervous system.