Document Detail


Receptor-mediated activation of Gsalpha: evidence for intramolecular signal transduction.
MedLine Citation:
PMID:  9614199     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To investigate the mechanism by which cell surface receptors activate heterotrimeric G proteins, we applied a scanning mutagenesis approach to the carboxyl-terminal 40% of alphas (residues 236-394) to identify residues that play a role in receptor-mediated activation. We identified four regions of sequence in which mutations significantly impaired receptor-dependent stimulation of cAMP synthesis in transiently transfected cyc- S49 lymphoma cells, which lack endogenous alphas. Residues at the carboxyl terminus are likely to be receptor contact sites. Buried residues near the bound GDP are connected to the carboxyl terminus by an alpha helix and may regulate GDP affinity. Residues in two adjacent loops of the GTPase domain at the interface with the helical domain, one of which includes a region, switch III, that changes conformation on GTP binding, are positioned to relay the receptor-initiated signal across the domain interface to facilitate GDP release. Consistent with this hypothesis, replacing the helical domain of alphas with that of alphai2 in an alphas/alphai2/alphas chimera corrects the defect in receptor-mediated activation caused by alphai2 substitutions on the GTPase side of the interface. Thus, complementary interactions between residues across the domain interface seem to play a role in receptor-catalyzed activation.
Authors:
S R Marsh; G Grishina; P T Wilson; C H Berlot
Related Documents :
8647889 - Cysteine34 of the cytoplasmic tail of the cation-dependent mannose 6-phosphate receptor...
11116139 - Functional rescue of the nephrogenic diabetes insipidus-causing vasopressin v2 receptor...
15163459 - A single amino acid change within the ion-channel domain of the gamma-aminobutyric acid...
9362389 - Mutations in the calcium-sensing receptor and their clinical implications.
10347189 - Phe310 in transmembrane vi of the alpha1b-adrenergic receptor is a key switch residue i...
10340379 - Cell specific transformation by c-fms activating loop mutations is attributable to cons...
14683689 - Expression, localization and function of prostaglandin receptors in myometrium.
16297559 - Effects of pre-treatment with amantadine on morphine induced antinociception during sec...
16870269 - Suppression of established experimental autoimmune encephalomyelitis and formation of m...
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  53     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1998 Jun 
Date Detail:
Created Date:  1998-06-25     Completed Date:  1998-06-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  981-90     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8026, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Cyclic AMP / metabolism
GTP Phosphohydrolases / chemistry
GTP-Binding Proteins / chemistry,  physiology*
Molecular Sequence Data
Protein Structure, Secondary
Receptors, Cell Surface / physiology*
Signal Transduction*
Structure-Activity Relationship
Transfection
Grant Support
ID/Acronym/Agency:
GM50369/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Cell Surface; 60-92-4/Cyclic AMP; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors.
Next Document:  A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity o...