Misrouted cell surface receptors as a novel disease aetiology and potential therapeutic target: the case of hypogonadotropic hypogonadism due to gonadotropin-releasing hormone resistance.
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.
Ulloa-Aguirre
Alfredo
A
Research Unit in Reproductive Medicine, Instituto Mexicano del Seguro Social, México DF.
Janovick
Jo Ann
JA
Leaños-Miranda
Alfredo
A
Conn
P Michael
PM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004351:Drug Resistance; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D005808:Genes, Recessive; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D011966:Receptors, LHRH / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D051399:Aquaporin 2; C505032:CFTR protein, human; D018832:Molecular Chaperones; D011956:Receptors, Cell Surface; D011966:Receptors, LHRH; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007987:Gonadotropin-Releasing Hormone; D012243:Rhodopsin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11