Inactivating mutations of G protein-coupled receptors and diseases: Structure-function insights and therapeutic implications
Introduction
G protein-coupled receptors (GPCRs) comprise the largest family of cell surface proteins, with more than 1000 members in humans. They transduce a large variety of extracellular signals, including light, smell, ions, catecholamines, neuropeptides, and large glycoprotein hormones (Bockaert & Pin, 1999). GPCRs consist of seven transmembrane Ī±-helices (TMs) connected by alternating extracellular and intracellular loops (ELs and ILs), with the N terminus extracellular and the C terminus intracellular. The crystal structure of rhodopsin at high resolution confirmed this topology (Palczewski et al., 2000). Almost all known physiological processes are regulated by GPCRs. Therefore it is easy to understand that defects in these signaling pathways will lead to various dysfunctions and diseases. Since the discovery of the first naturally occurring mutation in GPCRs causing human disease (Dryja et al., 1990), the list for diseases caused by GPCR mutations keeps expanding (for an exhaustive list see (Schoneberg et al., 2004)). A number of excellent reviews on diseased GPCRs have been published (Spiegel et al., 1993, Shenker, 1995, Spiegel, 1996, Schoneberg et al., 2002, Spiegel & Weinstein, 2004).
The purpose of this review is to summarize the studies in 15 GPCRs where multiple pathogenic loss-of-function mutations have been reported. Only overt mutations are covered. Polymorphic variants are not discussed herein. Interested readers are referred to recent reviews (Rana et al., 2001, Sadee et al., 2001). Based on the life cycle of the GPCRs, a general classification scheme is suggested for categorizing the ever-increasing mutations in these GPCRs. Insights that can be learned from the functional studies of the naturally occurring mutations in these GPCRs as well as the therapeutic implications are also highlighted.
Section snippets
Rhodopsin mutations and retinitis pigmentosa
Rhodopsin, the dim-light receptor, is one of the best-studied model systems in GPCRs. After absorption of light (photons), rhodopsin undergoes conformational changes and is converted to metarhodopsin II, the active form of rhodopsin. Metarhodopsin II activates the heterotrimeric G protein in rod cells, transducin, initiating the photo-transduction cascade.
The first mutation in GPCRs that cause human diseases was found in rhodopisn, P23H, causing autosomal dominant retinitis pigmentosa (ADRP) (
Towards a molecular classification of inactivating GPCR mutations
GPCRs begin their life with the transcription of their mRNAs in the nucleus and the synthesis of the polypeptides on the ribosome. These polypeptides are inserted into the ER membrane co-translationaly. Most of the GPCRs are glycoproteins. Therefore carbohydrates are added onto the polypeptides in the ER, specifically carbohydrates of the immature type containing high mannose. After initial folding, with the assistance of molecular chaperones such as calnexin and calreticulin, the receptors are
Insights into the structure-function of GPCRs
Careful characterizations of naturally occurring mutations of GPCRs that cause diseases not only provide novel insights into the physiological and pathophysiological roles of the underlying systems, but also shed lights on the structure-function relationships of the GPCRs. Experiments of nature provided us a lot of excellent clues. Below we summarize some of the lessons learned in these respects.
Class I mutants: Aminoglycosides
Although missense mutations are the most common loss-of-function mutations, a significant portion, which varies among the receptors, are nonsense and frameshift mutations that truncate the receptors prematurely. Previous studies in other genetic diseases caused by nonsense mutations discovered that aminoglycoside antibiotics, by binding to the decoding site on the ribosome, could decrease the codon-antocodon proofreading efficiency resulting in read-through of the premature stop codon. Using
Conclusions
During the past 15Ā years, an ever-expanding list of diseases caused by inactivating mutations in GPCRs has appeared in scientific literature. With a few exceptions (such as rhodopin, V2R, MC3R, and MC4R), the mode of inheritance is autosomal recessive for these diseases. Patients are either homozygous or compound heterozygous. We reviewed the literature where multiple mutations in 15 GPCRs have been identified to cause diseases. In vitro functional studies of these naturally occurring mutations
Acknowledgments
I sincerely apologize to those scientists whose outstanding contributions to this field could not be cited due to space limitations. Numerous investigators identified and functionally characterized rhodopsin and V2 receptor mutations that amounts to more than 100 each. It is not possible to cite all the relevant papers. I thank Dr. Deborah L. Segaloff for introducing me into the field of diseased GPCRs. My studies on the neural melanocortin receptors and human obesity, supported by American
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2022, Progress in Molecular Biology and Translational ScienceCitation Excerpt :These important studies revitalized the field of MC4R for obesity treatment, after the earlier disappointing results with another MC4R agonist that has significant side effects, including increased blood pressure and heart rate.116 With the classification of mutants as described above, different strategies can be devised to correct the defects.47 For Class I mutants due to premature stop codons, antibiotics can be used to decrease the codon-anticodon pairing fidelity and allow the translation to proceed through the premature termination codon to the natural termination codon.
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2022, Progress in Molecular Biology and Translational ScienceBiased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases
2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :In addition to Ī± subunit, Ī²Ī³ heterodimer mediates signaling processes and modulates activation of ion channels, such as G protein-regulated inwardly rectifying K+ channels [7] and Ca2+ channels [8] (reviewed in [9]). Naturally occurring mutations that affect GPCR signal transduction can cause either impaired or enhanced protein function, which are classified as loss-of-function or gain-of-function mutations, respectively [10ā14]. Loss-of-function mutations prevent signaling through several ways, such as defective receptor biosynthesis or trafficking, impairing ligand binding, and/or impairing basal or agonist-induced signaling [12,14,15].
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