, 2004). Hypocretin-2 enhances glutamate release by presynaptic actions in the ventral tegmental area, a region of the brain involved in reward and motivation, and also potentiates NMDA receptor actions in the postsynaptic cell

through activation of protein kinase C (Borgland et al., 2008). Peptides can modulate a number of different channels or transporters that regulate neuronal activity and spike probability, including sodium channels, nonselective cation channels, sodium-calcium exchangers, and voltage-dependent calcium channels. Many inhibitory neuropeptides reduce GABA or glutamate release by activating G protein-coupled inwardly rectifying K+ (GIRK) channels, also called Kir3 channels. GIRK channels DAPT datasheet have become increasingly recognized as playing important roles in both normal brain processes, and in disease states (Lüscher and Slesinger, 2010). Different GIRK channels arise from the heteromeric assembly of different subunits (Luján et al., 2009); after Gi/Go activation, Gβ and Selleckchem JQ1 Gγ bind to the GIRK channel, resulting in hyperpolarization and inhibition. GPCR kinases can block GPCR function by phosphorylation-mediated internalization of the receptor; recent evidence suggests that the GPCR kinases can also directly

and rapidly inactivate GIRK channels by competitively binding Gβ and Gγ subunits, thereby reducing GIRK channel activity (Raveh et al., 2010). Neuropeptides that inhibit neuronal activity by activating

however GIRK channels include NPY, somatostatin, opioid neuropeptides including dynorphin and met-enkephalin and others (Nakatsuka et al., 2008; Nassirpour et al., 2010; Li and van den Pol, 2008). On the other hand, excitatory neuropeptides such as substance P (Koike-Tani et al., 2005) and hypocretin (Hoang et al., 2003) also act on GIRK channels, but inhibit the GIRK current to increase neuronal activity. Coupling of receptors to ion channels may be different in different processes of the same cell. For instance, mu opioid receptors that respond to met-enkephalin and other related opioid peptides often show fast desensitization of GIRK currents (Williams et al., 2001). Mu opioid receptor responses desensitize rapidly in the POMC cell body; in contrast, mu receptor responses are resistant to desensitization in the context of reducing GABA release from presynaptic axon terminals synapsing with the recorded cell (Pennock et al., 2012). Many neurons contain multiple neuropeptides (Hökfelt et al., 1986, 1990; Skofitsch et al., 1985; Zupanc, 1996).