11-cis-retinal and Hypogonadism

Since the discovery of the first rhodopsin mutation that causes retinitis pigmentosa in 1990, significant progresses have been made in elucidating the pathophysiology of diseases caused by inactivating mutations of G protein-coupled receptors (GPCRs). This review aims to compile the compelling evidence accumulated during the past 15 years demonstrating the etiologies of more than a dozen diseases caused by inactivating GPCR mutations. A generalized classification scheme, based on the life cycle of GPCRs, is proposed. Insights gained through detailed studies of these naturally occurring mutations into the structure-function relationship of these receptors are reviewed. Therapeutic approaches directed against the different classes of mutants are being developed. Since intracellular retention emerges as the most common defect, recent progresses aimed at correcting this defect through membrane permeable pharmacological chaperones are highlighted.

Topics: Animals; Diabetes Insipidus, Nephrogenic; Dwarfism; Humans; Hypogonadism; Mutation; Obesity; Receptor, Melanocortin, Type 1; Receptor, Melanocortin, Type 2; Receptor, Melanocortin, Type 3; Receptor, Parathyroid Hormone, Type 1; Receptors, Calcium-Sensing; Receptors, CCR5; Receptors, G-Protein-Coupled; Receptors, LHRH; Receptors, Vasopressin; Retinitis Pigmentosa; Rhodopsin; Structure-Activity Relationship

Molecules that are incorrectly folded or defectively assembled are recognised by cellular quality control mechanisms. This leads such conformationally abnormal molecules to intracellular retention and eventual degradation. A number of diseases caused by mutations that interfere with proper processing and intracellular trafficking of key cell surface proteins have been described. These include a particular variant of hypogonadotropic hypogonadism, which results from mislocalisation of the gonadotropin-releasing hormone (GnRH) receptor. It has been shown recently that membrane expression and function of misfolded GnRH receptor mutants can be rescued by a peptidomimetic antagonist of GnRH (IN3) that permeates into the cell and reaches the abnormally manufactured nascent receptor, stabilising a conformation compatible with cell-surface transport and reversing intracellular retention. This approach seems applicable for the development of defined therapeutic strategies for an array of diseases caused by incorrectly routed cell surface or secreted proteins.

Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Aquaporin 2; Cell Membrane; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Drug Resistance; Genes, Recessive; Genetic Diseases, Inborn; Gonadotropin-Releasing Hormone; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Hypogonadism; Models, Molecular; Molecular Chaperones; Molecular Sequence Data; Mutation, Missense; Point Mutation; Protein Conformation; Protein Folding; Protein Transport; Receptors, Cell Surface; Receptors, LHRH; Rhodopsin; Signal Transduction; Structure-Activity Relationship