Figure 2.

GPCR localization influences compartmentalized signaling and neuronal hyper-excitability. Activation of GPCRs on central neurons by extracellular neuropeptides (e.g., NK₁R or CL/RAMP1) initiates cell surface-delimited G protein-dependent signaling events. This is followed by GPCR kinase (GRK) phosphorylation, arrestin-binding, and clathrin-mediated endocytosis into endosomes to promote the recruitment of unique signaling complexes and drive spatiotemporally distinct signaling that is associated with sustained excitability of neurons in spinal cord slice preparations (Jensen et al., 2017; Yarwood et al., 2017). Lipid conjugation can influence membrane partitioning of antagonists. Palmitoylated pepducins are proposed to inhibit G protein-mediated inflammatory processes on the cytoplasmic interface of the plasma membrane (PM); whereas the sterol moiety cholestanol increases drug accumulation in endosomes to enhance inhibition of sustained endosomal-delimited signaling.