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J. Biol. Chem., Vol. 269, Issue 37, 23032-23038, Sep, 1994
N Yuan, J Friedman, BS Whaley and RB Clark
Activation of cAMP-dependent protein kinase (cAPK) or protein kinase C
(PKC) causes a rapid desensitization of beta 2-adrenergic receptor (beta
AR) stimulation of adenylylcyclase in L cells, which previous studies
suggest involves the cAPK/PKC consensus phosphorylation site in the third
intracellular loop of the beta AR, RRSSK263. To determine the role of the
individual serines in the cAPK- and PKC-mediated desensitizations, wild
type (WT) and mutant beta ARs containing the substitutions,
Ser261-->Ala, Ser262-->Ala, Ser262-->Asp, and Ser261/262-
->Ala, were constructed and stably transfected into L cells. Results
showed that serine 262 was the primary site of the cAPK-induced
desensitization, whereas either serine 261 or serine 262 was sufficient to
confer the 4 beta-phorbol 12 beta-myristate 13 alpha-acetate
(PMA)/PKC-mediated desensitization. Coincident stimulation of cAPK and PKC
caused an additive desensitization (6-8-fold increase in the EC50) which
was significantly reduced (80%) only by the double substitution mutation.
Quantitative evaluation of the coupling efficiencies and the GTP-shift of
the WT and mutant receptors demonstrated that only one of the mutants,
Ser262-->Ala, was partially uncoupled. The Ser262-->Asp mutation did
not significantly uncouple, demonstrating that introducing a negative
charge did not appear to mimic the desensitized state of the receptor. The
beta AR expression level played a critical role in determining the pattern
of beta AR desensitization; i.e. while the overall desensitization was
unaltered within a large range of beta AR expression level (10-300
fmol/mg), the increase in EC50 and decrease in Vmax were differentially
affected by the change in the receptor level.
cAMP-dependent protein kinase and protein kinase C consensus site mutations of the beta-adrenergic receptor. Effect on desensitization and stimulation of adenylylcyclase
Graduate School of Biomedical Sciences, Department of Pharmacology, University of Texas Health Science Center at Houston 77225-0334.
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