title: Functional Significance of the Signal Peptides of Corticotropin-Releasing Factor Receptors.
abstract: The corticotropin releasing factor (CRF) receptors belong to the large family of G proteincoupled receptors (GPCRs) and must be transported to the plasma membrane to function properly. The first step of the intracellular transport of GPCRs is their insertion into the membrane of the endoplasmic reticulum (ER). This process is mediated by the translocon complex of the ER membrane and the signal sequences of the receptors. Most GPCRs possess signal sequences which form part of the mature proteins, the so called signal anchor sequences (usually transmembrane domain 1). The CRF receptors possess instead signal sequences at their extreme N tails which were thought to be cleaved off following integration of the receptors into the ER membrane (signal peptides, SPs, also called cleaved signal sequences). Recent work, however, showed that not all subtypes of CRF receptors stick to this rule. Whereas the corticotropin-releasing factor receptor type 1 (CRF1R) and the corticotropin-releasing factor receptor type 2b (CRF2(b)R) possess conventional SPs which are indeed cleaved off following ER insertion, the SP of the cortictropin-releasing factor receptor type 2a (CRF2(a)R) remains uncleaved. It forms a unique N-terminal domain (pseudo signal peptide, PSP) which has surprising functions beyond the ER level. Its presence not only influences expression levels at the plasma membrane but also receptor homodimerisation and, as a consequence, G protein selectivity. In this mini-review, we summarize the progress in understanding the functions of SPs of CRF receptors. Recent data also allow deriving hypotheses for a physiological significance of these sequences.
authors.affiliation: Leibniz-Institut Fur Molekulare Pharmakologie (FMP), Robert-Rossle-Str. 10, 13125 Berlin. Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schulein
authors.affiliation: Leibniz-Institut Fur Molekulare Pharmakologie (FMP), Robert-Rossle-Str. 10, 13125 Berlin. Germany.
authors.forename: Arthur
authors.initials: A
authors.lastname: Gibert
authors.affiliation: Leibniz-Institut Fur Molekulare Pharmakologie (FMP), Robert-Rossle-Str. 10, 13125 Berlin. Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rutz
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization; D021382:Protein Sorting Signals; D021381:Protein Transport; D018019:Receptors, Corticotropin-Releasing Hormone / Q000032:analysis / Q000378:metabolism*
chemical_list: D021382:Protein Sorting Signals; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone
keywords: CRF receptors; ER; GPCR; dimerisation; signal peptides; translocon