Binding to the GPCR induces a conformational change in the receptor, leading to activation of intracellular G proteins. Many G proteins exist in an inactive heterotrimeric form consisting of Gα, Gβ, and Gγ. Activation results in an exchange of GDP for GTP at the G protein’s α subunit and the dissociation of the G proteins from the GPCR. Peptide signaling is then amplified by the induction of multiple intracellular signaling

pathways that may involve adenylyl cyclase, cAMP, MAPK/ERK, PKA, and phosphorylation of a number of target proteins. Monomeric G proteins may also play a role in modulating some ion channels and actions of peptides ( Murray and O’Connor, 2004; Vögler et al., 2008; Thapliyal et al., 2008), and multiple G protein/effectors have been described for some neuropeptides, for instance GnRH ( Gardner and Pawson, 2009). Trametinib nmr The actions of neuropeptides on GPCRs can also Enzalutamide nmr be modulated at the receptor or effector level; for instance, members of the RGS (regulator of G protein signaling) family of proteins can

accelerate activation or deactivation of G proteins and may alter receptor-effector coupling ( Chuang et al., 1998; Doupnik et al., 2004; Labouèbe et al., 2007; Xie and Martemyanov, 2011). The literature on GPCRs is too voluminous to examine here, but has been addressed in some recent reviews ( Rosenbaum et al., 2009; Hazell et al., 2012). Peptide receptors are found heterogeneously distributed

throughout the brain, and can be expressed on cell bodies, dendrites, and axon terminals. Some peptides, for instance NPY, activate multiple different receptors expressed by target neurons, whereas others appear to act primarily on a ALOX15 single receptor, for instance kisspeptin acts primarily on GPR54. Our understanding of peptide receptor subcellular localization has lagged behind that of amino acid receptor localization, in part due to questionable specificity of some peptide receptor antisera. Perhaps the clearest picture that emerges of a class of neuronal GPCRs is for metabotropic glutamate receptors (mGluRs). These function similarly to neuropeptide GPCRs but are activated by glutamate and can act in an excitatory or inhibitory manner. Subcellular localization of mGluRs may provide some insight into the potential localization of neuropeptide GPCRs. Eight different mGluRs have been identified and, interestingly, are expressed in different regions of different neurons. mGluR7, for instance, is often found at the presynaptic active zone (Schoepp, 2001) and mGluR4, -7α, and -8α are found on the presynaptic active zone of inhibitory axons, and only those innervating other GABA interneurons but not those innervating excitatory pyramidal cells (Kogo et al., 2004). mGluR1α is found on the postsynaptic membrane at the periphery of the synapse active zone (Baude et al.