Homologous or agonist-specific desensitization is a widespread process that causes specific dampening of cellular
responses to stimuli such as hormones, neurotransmitters, or sensory signals. It is defined by a loss of responsiveness of
receptors that have been continuously or repeatedly stimulated, while the responses of other receptors remain intact.
Homologous desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, called
beta-adrenergic receptor kinase (BARK, or ADRBK1). A cofactor is required for this kinase to inhibit receptor
function. Lohse et al. (1990) cloned the cDNA for this cofactor and found that it encodes a 418-amino acid protein
homologous to the retinal protein arrestin. The purified protein, beta-arrestin, inhibited the signaling function of
BARK-phosphorylated beta-adrenergic receptors by more than 75%, but not that of rhodopsin.
NCBI Summary:
Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. Arrestin beta 1 is a cytosolic protein and acts as a cofactor in the beta-adrenergic receptor kinase (BARK) mediated desensitization of beta-adrenergic receptors. Besides the central nervous system, it is expressed at high levels in peripheral blood leukocytes, and thus the BARK/beta-arrestin system is believed to play a major role in regulating receptor-mediated immune functions. Alternatively spliced transcripts encoding different isoforms of arrestin beta 1 have been described, however, their exact functions are not known.
General function
Intracellular signaling cascade
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle development, Ovulation
Comment
Mukherjee S, et al 1999
reported that beta-arrestin-dependent desensitization of luteinizing
hormone/choriogonadotropin receptor is prevented by a synthetic peptide
corresponding to the third intracellular loop of the receptor.
They reported for the luteinizing hormone/choriogonadotropin receptor (LH/CG R) that beta-arrestin tightly
bound to porcine ovarian follicular membranes mediates agonist-dependent desensitization of LH/CG
R-stimulated adenylyl cyclase (AC) activity and show that addition of a synthetic peptide corresponding to the entire third
intracellular loop (3i) of the LH/CG R completely and specifically reverses desensitization of AC
activity, with an ED50 of 10 microM but does not modulate basal, hCG-stimulated, or
forskolin-stimulated AC activities. beta-Arrestin binds selectively to the 3i peptide coupled to
activated Sepharose. Desensitization of LH/CG R-stimulated AC activity is rescued when the 3i
peptide is preincubated with exogenous beta-arrestin.
Expression regulated by
Comment
Ovarian localization
Granulosa, Luteal cells
Comment
Mukherjee S, et al reported a direct role for arrestins in desensitization of the luteinizing
hormone/choriogonadotropin receptor in porcine ovarian follicular membranes.
Based on evidence that porcine ovarian follicular membranes unexpectedly
contained beta-arrestin-1, the role of arrestins in desensitization of the LH/CG R was investigated.
Results showed that neutralizing arrestin antibodies blocked the development of desensitization and
that desensitization was rescued with a synthetic peptide corresponding to the antibody-binding
epitope on beta-arrestin-1. These results suggest that endogenous beta-arrestin-1 participates in
agonist-dependent desensitization of the LH/CG R. Addition of recombinant purified beta-arrestin-1
mimicked human chorionic gonadotrophin to promote desensitization of human chorionic
gonadotrophin-stimulated AC activity, in the presence of the ATP phosphorylation antagonist
adenylyl-imidodiphosphate, with an ED50 of approximately 0.1 nM. Increased levels of an 87-kDa
protein reactive with glycoprotein hormone R-reactive antibody, consistent with the LH/CG R,
coimmunoprecipitated with follicular membrane beta-arrestin-1 in response to LH/CG R activation
compared with unactivated R.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:Conner et al. (1997) prepared beta-arrestin-1 knockout
mice to define the physiologic role of beta-arrestin-1 in the regulation of G protein-coupled receptors such as the
beta-adrenergic receptor. Homozygous mutants were structurally normal and had normal life spans. They displayed
normal resting cardiovascular parameters but were more sensitive to beta-receptor agonist-stimulated increases in
cardiac ejection fraction, consistent with a role for beta-arrestin-1 in beta-adrenergic receptor desensitization.