The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

Abstract

GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.

Mutation of GPR143 Associated With Ocular Albinism Type 1, Intellectual Disability, and Schizophrenia: The Complex Biological and Social Interactions Between Genetic Syndromes and Mental Illness

“…First, it is possible that the deletion of exons 2 to 8 of GPR143 , presumably resulting in a complete loss of expression of the protein in males, directly contributed to the patient’s psychopathology. The protein encoded by GPR143 is widely distributed in the central and peripheral nervous system and may function as an L-DOPA receptor in vivo 13,14. L-DOPA is a precursor of dopamine synthesis and may also itself have a neurotransmitter function.…”

“…The protein encoded by GPR143 is widely distributed in the central and peripheral nervous system and may function as an L-DOPA receptor in vivo. 13,14 L-DOPA is a precursor of dopamine synthesis and may also itself have a neurotransmitter function. GPR143 immunoreactive cells have been detected in the hippocampus, cerebral cortex, striatum, substantia nigra, hypothalamic median eminence, suprachiasmatic nucleus, caudal ventrolateral medulla, and olfactory bulb, 13 reflecting regions involved in multiple circuits of neuropsychiatric interest.…”

“…Given the hypothesis that dysregulated dopaminergic function underlies positive symptoms of psychotic disorders,15,16 it is possible that GPR143 dysfunction could have a direct etiologic role in psychosis. In addition, GPR143 may have a function in neurodevelopment,14 also potentially linking its loss to neuropsychiatric disorders. However, there are no reports in the literature of psychiatric phenomena or cognitive deficits associated with GPR143 mutations, including in patients with the same deletion detected in our patient 17,18.…”

A Network of MicroRNAs and mRNAs Involved in Melanosome Maturation and Trafficking Defines the Lower Response of Pigmentable Melanoma Cells to Targeted Therapy

“…GPR143/OA1 is a melanosome G-protein-coupled receptor, whose mutations have been associated with type I ocular albinism [62]. GPR143 protein sustains MITF expression, and hence PMEL expression, therefore contributing to correct melanosome maturation [63].…”