Desensitization of G Protein–coupled Receptors and Neuronal Functions

Abstract

I Abstract G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and βarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or βarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and µ-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and βarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

“…Moderate intensity stimulation would provide sufficient activation with minimal desensitization, while high levels of stimulation would result in overactivation and reduction of the response. G protein-coupled receptors, such as those which likely mediate the response to VNSdependent engagement of the cholinergic and noradrenergic systems, exhibit notable desensitization and may explain the inverted-U response to VNS [139,140]. While these models can account for the inverted-U, they are not mutually exclusive and various other systems likely contribute.…”

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

“…In in vitro cellular systems, expression of G protein-coupled receptor kinase 2 (GRK2) enhanced phosphorylation and regulation of MOR [34,35], and most of GRK2 was shown to be not associated with rafts [36]. Since GRK2 is ubiquitously expressed in the brain, this regulation was expected to occur in vivo [37]. Thus, a simple hypothesis is that thalamus has more MOR in non-rafts membranes, where the bulk of GRK2 resides, and thereby gets phosphorylated and desensitized more readily than MOR in CPu, which is mostly located in rafts and less accessible to the kinase.…”

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

“…Once activated, many G protein-coupled receptors are phosphorylated by G protein receptor kinases, followed by recruitment of arrestins and endocytosis (Gainetdinov et al, 2004;Luttrell and Lefkowitz, 2002). Internalized receptors can be sorted to distinct endosomal compartments where they are either dephosphorylated and recycled back to the plasma membrane or targeted to lysosomes for degradation.…”