Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons.

The lateral hypothalamus (LH) is an important area in physiological homeostasis. In addition to its role in functions such as sensorimotor integration, sleep and arousal, there is a growing body of evidence suggesting that the LH plays a crucial part in the complex network involved in the regulation of energy homeostasis (Sawchenko, 1998). One of the few neuropeptides synthesized only in the LH area is melanin-concentrating hormone (MCH), a cyclic 19-amino-acid peptide that has recently generated considerable attention due to its robust effects on feeding. Intracerebral administration of MCH has been reported to evoke feeding in rodents (Qu et al. 1996; Rossi et al. 1997). In transgenic mice that overexpress MCH in the LH area, obesity and resistance to insulin have been observed (Ludwig et al. 2001). Conversely, MCH-deficient mice have reduced body weight and are lean due to decreased feeding and an enhanced metabolism (Shimada et al. 1998). MCH mRNA expression is increased by starvation, and c-fos in MCH neurons is upregulated by starvation (Qu et al. 1996) and by leptin administration (Huang & Viale, 1999). MCH has been reported to modify memory retention (Monzon et al. 1999). MCH expression levels show sensitivity to oestrogenic steroids (Viale et al. 1999) and MCH stimulates the release of gonadotropin-releasing hormone and gonadotropins in the female rat (Chiocchio et al. 2001), indicating an involvement in the reproductive axis. MCH-immunoreactive axons have a remarkably wide distribution throughout the CNS. In addition to a high density of fibres and boutons in the LH, it has been shown that MCH-containing fibres project to the isocortex, olfactory regions, hippocampus, amygdala, septum, basal ganglia, thalamus, brainstem, cerebellum and spinal cord (Bittencourt et al. 1992). The MCH receptor, SLC-1, also has a widespread pattern of expression, correlating with the distribution of MCH axons throughout the CNS (Lembo et al. 1999; Kilduff & De Lecea, 2001; Saito et al. 2001). Previous work with the MCH receptor expressed in non-neuronal cells transfected with the receptor gene, SLC-1, has led to the view that MCH increases cellular calcium levels, as detected with digital imaging, and increases potassium currents (Bachner et al. 1999). We have shown that in neurons, MCH exerts an inhibitory modulation of synaptic activity (Gao & van den Pol, 2001), and in contrast to work on non-neuronal cells, our preliminary data suggested that inhibition of voltage-dependent calcium currents underlies the MCH-induced actions in neurons. Voltage-dependent calcium channels are important participants in neuronal function. Voltage-dependent N- and P/Q-type calcium channels play a substantial role in action-potential-dependent transmitter release (Wheeler et al. 1994; Catterall, 1998), and L-type calcium channels may modulate the expression of transporters and channels (Carafoli et al. 1999). Peptides that modulate calcium channels are therefore in a critical position to regulate a number of dimensions of neuronal activity and function. Despite its important role in the modulation of many neuronal systems within the brain, as revealed at both the molecular and whole-animal level, little is known about how MCH works at the cellular level. In the study presented here, we have examined the cellular actions of MCH in LH cultures and slices. We have characterized the inhibitory mechanism and signal transduction of MCH on specific voltage-dependent calcium currents with whole-cell patch recording.