The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine determines the function of nigrostriatal system
for motor coordination. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in SNc. One practical approach for alleviation of PD symptoms is to enhance the excitability of surviving dopaminergic neurons in SNc where the neuronal activity can be modulated by a variety of neurotransmitters, endogenous hormones and peptides. The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the SNc. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a-activated PLC-PKC pathway. Brain slice recordings of SNc neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into SNc results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signaling is likely a common pathway utilized by the nervous system.