While a specific CART receptor(s) has not been identified to date, there is strong evidence that CART signaling can be blocked by pertussis toxin (PTX), indicative of the involvement of an inhibitory G-protein-coupling receptor that couples to Gi/o proteins (Yermolaieva et al., 2001; Lakatos et al., 2005; Sen et al., 2007). For example, CART I (55–102) has been described to inhibit voltage-gated L-type Ca2+ channels in hippocampal neurons, an effect that was blocked by treatment with PTX (Yermolaieva et al., 2001). Furthermore, central administration of CART I (55–102) stimulated the phosphorylation of cyclic AMP-response-element-binding protein (CREB) in CRH neurons in the PVN of fasted and fed rats (Sarkar et al., 2004), which again is classified as a PTX-sensitive mechanism. Finally, CART I (55–102) application activated extracellular signal-regulated kinase (ERK) phosphorylation in the rodent pituitary-derived cell lines, AtT20 and GH3, and such CART-induced effects were attenuated by a MEK kinase inhibitor as well as pre-treatment with PTX (Lakatos et al., 2005), further supporting the mediation of CART action by inhibitory G proteins.