PMID- 10212248
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 18
DP  - 1999 Apr 30
TI  - A gain-of-function polymorphism in a G-protein coupling domain of the human
      beta1-adrenergic receptor.
PG  - 12670-4
AB  - The beta1-adrenergic receptor (beta1AR) is a key cell surface signaling protein
      expressed in the heart and other organs that mediates the actions of
      catecholamines of the sympathetic nervous system. A polymorphism in the
      intracellular cytoplasmic tail near the seventh transmembrane-spanning segment of
      the human beta1AR has been identified in a cohort of normal individuals. At amino
      acid position 389, Gly or Arg can be found (allele frequencies 0.26 and 0. 74,
      respectively), the former previously considered as the human wild-type beta1AR.
      Using site-directed mutagenesis to mimic the two variants, CHW-1102 cells were
      permanently transfected to express the Gly-389 and Arg-389 receptors. In
      functional studies with matched expression, the Arg-389 receptors had slightly
      higher basal levels of adenylyl cyclase activities (10.7 +/- 1.2 versus 6.1 +/-
      0.4 pmol/min/mg). However, maximal isoproterenol-stimulated levels were markedly 
      higher for the Arg-389 as compared to the Gly-389 receptor (63.3 +/- 6.1 versus
      20.9 +/- 2.0 pmol/min/mg). Agonist-promoted [35S]guanosine
      5'-O-(thiotriphosphate) binding was also increased with the Arg-389 receptor
      consistent with enhanced coupling to Gs and increased adenylyl cyclase
      activation. In agonist competition studies carried out in the absence of
      guanosine 5'-(beta, gamma-imido)triphosphate, high affinity binding could not be 
      resolved with the Gly-389 receptor, whereas Arg-389 displayed an accumulation of 
      the agonist high affinity receptor complex (RH = 26%). Taken together, these data
      indicate that this polymorphic variation of the human beta1AR results in
      alterations of receptor-Gs interaction with functional signal transduction
      consequences, consistent with its localization in a putative G-protein binding
      domain. The genetic variation of beta1AR at this locus may be the basis of
      interindividual differences in pathophysiologic characteristics or in the
      response to therapeutic betaAR agonists and antagonists in cardiovascular and
      other diseases.
FAU - Mason, D A
AU  - Mason DA
AD  - Departments of Medicine and Pharmacology, University of Cincinnati College of
      Medicine, Cincinnati, Ohio 45267, USA.
FAU - Moore, J D
AU  - Moore JD
FAU - Green, S A
AU  - Green SA
FAU - Liggett, S B
AU  - Liggett SB
LA  - eng
SI  - GENBANK/AF169007
GR  - HL41496/HL/NHLBI NIH HHS/United States
GR  - HL52318/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adrenergic beta-Agonists)
RN  - 0 (Receptors, Adrenergic, beta-1)
RN  - 34273-04-6 (Guanylyl Imidodiphosphate)
RN  - 9007-49-2 (DNA)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Adenylyl Cyclases/metabolism
MH  - Adrenergic beta-Agonists/pharmacology
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Arginine/chemistry/metabolism
MH  - Base Sequence
MH  - COS Cells
MH  - DNA
MH  - Enzyme Activation
MH  - GTP-Binding Proteins/chemistry/*metabolism
MH  - Glycine/chemistry/metabolism
MH  - Guanylyl Imidodiphosphate/pharmacology
MH  - Humans
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - *Polymorphism, Genetic
MH  - Receptors, Adrenergic, beta-1/chemistry/*metabolism
MH  - Sequence Homology, Amino Acid
EDAT- 1999/04/23 00:00
MHDA- 1999/04/23 00:01
CRDT- 1999/04/23 00:00
PHST- 1999/04/23 00:00 [pubmed]
PHST- 1999/04/23 00:01 [medline]
PHST- 1999/04/23 00:00 [entrez]
AID - 10.1074/jbc.274.18.12670 [doi]
AID - S0021-9258(19)73403-6 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 30;274(18):12670-4. doi: 10.1074/jbc.274.18.12670.