Characterization of structural determinants of type 1 corticotropin releasing hormone (CRH) receptor signalling
Danijela Markovic1, Dimitris K Grammatopoulos
1Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK. mdanijela73@googlemail.com
Abstract:
Mammalian adaptation to stressful stimuli requires activation of the type 1 corticotropin releasing hormone (CRH) receptor (CRH-R1), a 415 amino acid protein that belongs to the large superfamily of 7 transmembrane domain receptors that relay signals across cells through activation of G-proteins. CRH-R1 expression and activity is regulated at the gene level by mRNA alternative splicing that results in a number of CRH-R1 variants. This process can generate putative CRH-R1 receptor variants with distinct structural and signaling properties; their study can provide important insights about the structural determinants of CRH-R1 functional characteristics. Using site-directed mutagenesis by overlap extension polymerase chain reaction (OE-PCR), we investigated the structure-function relationships of a CRH-R1 variant with an extended 1st intracellular loop (IC1) (CRH-R1beta), a sequence modification that impairs signaling activity (such as cAMP production and MAPK activation). We identified a penta-amino acid cassette within the 29-amino acid insert of CRH-R1beta rich in positive charged amino acids (F(170)-R(174)), as an important structural determinant for the impaired cAMP response.
Related Concept Videos
Intracellular Hormone Receptors
The Two-State Receptor Model
The binding affinity of a drug determines its interaction with one...
Transducer Mechanism: G Protein–Coupled Receptors
GPCRs are also called heptahelical, 7TM, or...
G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Cushing Syndrome II: Pathophysiology
Adrenergic Receptors: β Subtype
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...


