The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta (SNc), where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. However, how ghrelin regulates the excitability of dopaminergic neurons remains unknown. 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 slices of the SNc were prepared from SD rats of postnatal 10 days. Nystatin-perforated patch clamp recordings of SNc neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents from 25.4 ± 3 pA to 12.1 ± 2.1 pA (n=8, p<0.01, Values are means ± S.E.M., compared by Paired t-test.). This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice (6-7-week old rQ2-G279S transgenic mice with background of TB6D2F1/Crl * C57/B6) or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, adult female Wistar rats weighing 200-250 g were anesthetized with chloral hydrate (400 mg/kg, i.p.). Intracerebroventricular ghrelin administration (100 nM or 1000 nM, 5 μl) causes increased dopamine release from 1.3 ± 0.2 μM to 3.9 ± 0.5 μM (n=6, p<0.05, Values are means ± S.E.M.) and turnover (n=6, p<0.05) in the striatum. Microinjection of ghrelin (1000 nM, 0.5 μl) or XE991 (1 μM, 0.5 μl) into SNc results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Taken together, our findings reveal that ghrelin exerts its function by inhibiting voltage-gated Kv7/KCNQ/M-channel, resulting in enhanced excitability of nigral dopaminergic neurons for improvement of motor impairment. The ghrelin/KCNQ signaling is likely a common pathway utilized by the nervous system.