Abstract:
:Although palmitoylation of the beta(2)-adrenergic receptor (beta(2)AR), as well as its phosphorylation by the cyclic AMP-dependant protein kinase (PKA) and the beta-adrenergic receptor kinase (beta ARK), are known to play important roles in agonist-promoted desensitization, their relative contribution and mutual regulatory influences are still poorly understood. In this study, we investigated the role that the carboxyl tail PKA site (Ser(345,346)) of the beta(2)AR plays in its rapid agonist-promoted phosphorylation and desensitization. Mutation of this site (Ala(345,346)beta(2)AR) significantly reduced the rate and extent of the rapid desensitization promoted by sustained treatment with the agonist isoproterenol. The direct contribution of Ser(345,346) in desensitization was then studied by mutating all other putative PKA and beta ARK phosphorylation sites (Ala(261,262)beta ARK(-)beta(2)AR). We found this mutant receptor to be phosphorylated upon receptor activation but not following direct activation of PKA, suggesting a role in receptor-specific (homologous) but not heterologous phosphorylation. However, despite its phosphorylated state, Ala(261,262)beta ARK(-)beta(2)AR did not undergo rapid desensitization upon agonist treatment, indicating that phosphorylation of Ser(345,346) alone is not sufficient to promote desensitization. Taken with the observation that mutation of either Ser(345,346) or of the beta ARK phosphorylation sites prevented both the hyper-phosphorylation and constitutive desensitization of a palmitoylation-less mutant (Gly(341)beta(2)AR), our data suggest a concerted/synergistic action of the two kinases that depends on the palmitoylation state of the receptor. Consistent with this notion, in vitro phosphorylation of Gly(341)beta(2)AR by the catalytic subunit of PKA facilitated further phosphorylation of the receptor by purified beta ARK. Our study therefore allows us to propose a coordinated mechanism by which sequential depalmitoylation, and phosphorylation by PKA and beta ARK lead to the functional uncoupling and desensitization of the ss(2)AR.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Moffett S,Rousseau G,Lagacé M,Bouvier Mdoi
10.1046/j.1471-4159.2001.00005.xkeywords:
subject
Has Abstractpub_date
2001-01-01 00:00:00pages
269-79issue
1eissn
0022-3042issn
1471-4159journal_volume
76pub_type
杂志文章abstract::The ability of cholinergic vesicles to incorporate acetylcholine (ACh) was studied using highly purified synaptic vesicles from Torpedo electric organ. Depleted vesicles were capable of rapidly taking up exogenous ACh. Evidence that this represented true incorporation was that labelled ACh comigrated with vesicular AT...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1981.tb00479.x
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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doi:10.1046/j.1471-4159.1994.63041477.x
更新日期:1994-10-01 00:00:00
abstract::The rat substance P (SP) receptor (SPR) was expressed in insect Sf9 cells by infection with recombinant baculovirus. The receptor bound SP with high affinity (KD = 360 pM) and had a rank order of affinity of SP > neurokinin A > neurokinin B. Ligand activation of the receptor resulted in an increase in both inositol li...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1995.64041622.x
更新日期:1995-04-01 00:00:00
abstract::The NMDA receptor exhibits increased sensitivity to stimulation during early development compared with the adult. In this study, we examined modulation of the NMDA receptor by polyamines during development to see if it correlates with differences in the functional responsiveness of the NMDA receptor. [3H]MK-801 bindin...
journal_title:Journal of neurochemistry
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doi:10.1046/j.1471-4159.1994.62041408.x
更新日期:1994-04-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1981.tb01654.x
更新日期:1981-02-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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更新日期:2008-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1111/j.1471-4159.2006.03886.x
更新日期:2006-07-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb10929.x
更新日期:1989-01-01 00:00:00
abstract::Overexpression of gp120, the major coat protein of the HIV-1 virus, in central glial cells, or treatment of neurons with gp120 in culture, produces apoptotic neuronal death. Here we demonstrate that CEP-1347 (KT7515), an inhibitor of mixed lineage kinase 3 (MLK3), an upstream activator of JNK, inhibits gp120IIIB-induc...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2002.01088.x
更新日期:2002-09-01 00:00:00
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journal_title:Journal of neurochemistry
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doi:10.1111/j.1471-4159.2008.05289.x
更新日期:2008-06-01 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1046/j.1471-4159.2000.0741000.x
更新日期:2000-03-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2000.0741621.x
更新日期:2000-04-01 00:00:00
abstract::To explore the hypothesis that alterations in cellular membrane lipids are present at the stage of pre-clinical Alzheimer's disease (AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed targeted shotgun lipidomics of lipid extracts from post-mortem brains of subjects with pre-clinical AD. ...
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01697.x
更新日期:2003-04-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2001.00612.x
更新日期:2001-11-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1999.0721088.x
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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更新日期:2008-12-01 00:00:00
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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更新日期:1986-08-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2006.04161.x
更新日期:2006-12-01 00:00:00
abstract::SH-SY5Y neural cells expressing mu- and delta-opioid receptors were maintained viable in isotonic, sodium-free buffer in vitro. Intracellular sodium levels were manipulated by various methods, and ligand binding to intact cells was studied. In physiological buffer containing 118 mM sodium, [3H]Tyr-D-Ala-Gly-(Me)Phe-Gl...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.68031053.x
更新日期:1997-03-01 00:00:00