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Biomedical subjects

M M Kwatra

Publications and source records attributed to M M Kwatra.

At least 19 recordsLinked to original sources
PubMed2000

Beta(2)-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G(s) and G(i).

Cardiac G protein-coupled receptors that couple to Galpha(s) and stimulate cAMP formation (eg, beta-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the beta(2)-adrenergic receptor (AR), also couples to the inhibitory G protein Galpha(i) (activation of which inhibits cAMP formation). If beta(2)ARs could be shown to couple to Galpha(i) in the human heart, it would have important ramifications, because levels of Galpha(i) increase with age and in failing human heart. Therefore, we investigated whether beta(2)ARs in the human heart activate Galpha(i). By photoaffinity labeling human atrial membranes with [(32)P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Galpha(i), we found that Galpha(i) is activated by stimulation of beta(2)ARs but not of beta(1)ARs. In addition, we found that other Galpha(s)-coupled receptors also couple to Galpha(i), including histamine, serotonin, and glucagon. When coupling of these receptors to Galpha(i) is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that beta(2)AR and many other Galpha(s)-coupled receptors in human atrium also couple to Galpha(i) and that abolishing the coupling of these receptors to Galpha(i) increases the receptor-mediated adenylyl cyclase activity.

Adenylate Cyclase Toxin↗
PubMed1999

Real-time visualization of the cellular redistribution of G protein-coupled receptor kinase 2 and beta-arrestin 2 during homologous desensitization of the substance P receptor.

The substance P receptor (SPR) is a G protein-coupled receptor (GPCR) that plays a key role in pain regulation. The SPR desensitizes in the continued presence of agonist, presumably via mechanisms that implicate G protein-coupled receptor kinases (GRKs) and beta-arrestins. The temporal relationship of these proposed biochemical events has never been established for any GPCR other than rhodopsin beyond the resolution provided by biochemical assays. We investigate the real-time activation and desensitization of the human SPR in live HEK293 cells using green fluorescent protein conjugates of protein kinase C, GRK2, and beta-arrestin 2. The translocation of protein kinase C betaII-green fluorescent protein to and from the plasma membrane in response to substance P indicates that the human SPR becomes activated within seconds of agonist exposure, and the response desensitizes within 30 s. This desensitization process coincides with a redistribution of GRK2 from the cytosol to the plasma membrane, followed by a robust redistribution of beta-arrestin 2 and a profound change in cell morphology that occurs after 1 min of SPR stimulation. These data establish a role for GRKs and beta-arrestins in homologous desensitization of the SPR and provide the first visual and temporal resolution of the sequence of events underlying homologous desensitization of a GPCR in living cells.

Arrestins↗
PubMed1999

Characterization of differences between rapid agonist-dependent phosphorylation and phorbol ester-mediated phosphorylation of human substance P receptor in intact cells.

Substance P receptor (SPR), which plays a key role in pain transmission, is known to undergo rapid agonist-dependent desensitization and internalization. The present study shows that human SPR undergoes agonist-dependent phosphorylation in intact cells. Immunoprecipitation of SPR from 32Pi-labeled Chinese hamster ovary cells stably expressing human SPR (CHO-hSPR) indicates that substance P (SP) causes a rapid (T1/2 < 1 min), dose-dependent (EC50 = 2 nM), and pronounced (5-fold over basal) phosphorylation of SPR. Because SPR in CHO-hSPR couples to Galphaq, Galphas, and Galphao (), we examined the involvement of various second messenger-activated protein kinases in SPR phosphorylation. Although increases in intracellular cyclic AMP or treatment with the calcium ionophore A23187 do not cause SPR phosphorylation, treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) causes a 2.5-fold increase in SPR phosphorylation with a T1/2 of <1 min. However, PKC inhibitor GF109203X has no effect on SP-dependent SPR phosphorylation. Furthermore, although SP treatment phosphorylates SPR on both serine and threonine residues equally, PMA treatment phosphorylates the receptor predominantly on serine residues. Two-dimensional phosphopeptide mapping data indicate that SP-dependent and PMA-dependent phosphorylations of SPR have some unique differences. Taken together, these data suggest that although activation of PKC by PMA can lead to SPR phosphorylation, PKC does not mediate SP-dependent phosphorylation of SPR. In conclusion, the present study represents the first demonstration and characterization of agonist-dependent and PMA-mediated phosphorylation of SPR in intact cells.

Animals↗
PubMed1998

Acute myocardial beta-adrenergic receptor dysfunction after cardiopulmonary bypass in patients with cardiac valve disease. Duke Heart Center Perioperative Desensitization Group.

BACKGROUND: Patients with cardiac valve disease (CVD) frequently have congestive heart failure (CHF) and chronic myocardial beta-adrenergic receptor (beta AR) desensitization. Cardiac surgery requiring cardiopulmonary bypass (CPB) is associated with increased plasma catecholamine concentrations, which might worsen myocardial beta AR function. We therefore tested the hypothesis that acute beta AR dysfunction occurs during CPB in patients with CVD. METHODS AND RESULTS: After informed consent, 50 patients were enrolled. Right atrial biopsy samples were obtained at initiation and conclusion of CPB to assess beta AR density and adenylyl cyclase (AC) activity. Plasma catecholamine concentrations increased 3-fold during CPB (P < 0.01). Although beta AR density remained constant, isoproterenol-stimulated AC activity decreased significantly (approximately 30%; P < 0.005). AC activity decreased 22% and 24% with direct G protein (NaF) or AC (manganese) activation, respectively. Patients with or without preoperative CHF exhibited similar degrees of acute myocardial beta AR dysfunction during CPB. CONCLUSIONS: Acute myocardial beta AR dysfunction occurs during CPB in patients with severe CVD requiring surgical correction, with or without preexisting CHF. The primary underlying mechanism involves functional uncoupling of the beta AR signal transduction pathway at the level of the AC moiety. This information should facilitate development of agents designed to prevent acute myocardial beta AR dysfunction during CPB, potentially leading to improved outcome in this high-risk population.

Aged↗
PubMed1998

Human substance P receptor expressed in Chinese hamster ovary cells directly activates G(alpha q/11), G(alpha s), G(alpha o).

Substance P receptor (SPR) stably expressed in Chinese hamster ovary (CHO) cells stimulates at least three second messenger systems including phosphoinositide hydrolysis, cyclic AMP (cAMP) formation, and arachidonic acid release. Whether these second messenger systems are activated via single or multiple G proteins is not known. Therefore, in the present study we examined whether human SPR (hSPR) stably expressed in CHO cells activates multiple G proteins. This was achieved by photoaffinity labeling of G(alpha)-subunits with [32P]azidoanilido-GTP ([32P]AA-GTP) upon hSPR stimulation in CHO-hSPR membranes followed by immunoprecipitation of the labeled G(alpha)-subunits with antibodies specific for various G(alpha)-subunits. These experiments reveal that hSPR directly activates G(alpha q/11), G(alpha s) and G(alpha o). While hSPR is known to couple G(alpha q/11), the present study provides the first evidence that hSPR can also activate G(alpha s) and G(alpha o) in a mammalian system.

Amino Acid Sequence↗
PubMed1998

Characterization of GRK2-catalyzed phosphorylation of the human substance P receptor in Sf9 membranes.

G protein-coupled receptor kinases (GRKs) phosphorylate agonist-occupied G protein-coupled receptors (GPCRs), resulting in GPCR desensitization. GRK2 is one of the better studied of the six known GRKs and phosphorylates several GPCRs. In a previous study, we documented that GRK2 and GRK3 phosphorylate purified and reconstituted rat substance P receptor (rSPR) [Kwatra et al. (1993) J. Biol. Chem. 268, 9161-9164]. Here, we characterize in detail GRK2-catalyzed phosphorylation of human SPR (hSPR) in intact membranes. GRK2 phosphorylates hSPR in urea-washed Sf9 membranes in an agonist-dependent manner with a stoichiometry of 19 +/- 1 mol of phosphate/mol of receptor, which increases slightly (1.3-fold increase) in the presence of G beta gamma. Kinetic analyses indicate that receptor phosphorylation occurs with a Km of 6.3 +/- 0.4 nM and a Vmax of 1.8 +/- 0.1 nmol/min/mg; these kinetic parameters are only slightly affected by G beta gamma [Km = 3.6 +/- 1.0 nM and Vmax = 2.2 +/- 0.2 nmol/min/mg]. The lack of a strong stimulatory effect of G beta gamma on GRK2-catalyzed phosphorylation of hSPR is surprising since G beta gamma potently stimulates GRK2-catalyzed phosphorylation of beta 2-adrenergic receptor and rhodopsin. Involvement of G beta gamma endogenously present in membranes is ruled out as a source of high levels of hSPR phosphorylation, since receptor phosphorylation was not affected by guanine nucleotides that suppress or enhance the release of endogenous G beta gamma. The present study determines, for the first time, the kinetics of phosphorylation of a receptor substrate of GRK2 in intact membranes. Further, our results identify hSPR as a unique substrate of GRK2 whose phosphorylation is strong even in the absence of G beta gamma.

Amino Acid Sequence↗
PubMed1998

Acute depression of myocardial beta-adrenergic receptor signaling during cardiopulmonary bypass: impairment of the adenylyl cyclase moiety. Duke Heart Center Perioperative Desensitization Group.

BACKGROUND: Previously the authors showed that myocardial beta-adrenergic (betaAR) function is reduced after cardiopulmonary bypass (CPB) in a canine model Whether CPB results in similar effects on betaAR function in adult humans is not known. Therefore the current study tested two hypotheses: (1) That myocardial betaAR signaling is reduced in adult humans after CPB, and (2) that administration of long-term preoperative betaAR antagonists prevents this process. METHODS: After they gave informed consent, 52 patients undergoing aortocoronary surgery were enrolled. Atrial biopsies were obtained before CPB and immediately before discontinuation of CPB. Plasma catecholamine concentrations, myocardial betaAR density, and functional responsiveness (basal, isoproterenol, zinterol, sodium fluoride, and manganese-stimulated adenylyl cyclase activity) were assessed. RESULTS: Catecholamine levels increased significantly during CPB (P < 0.005). Myocardial betaAR adenylyl cyclase coupling decreased during CPB, as evidenced by a 21% decrease in isoproterenol-stimulated adenylyl cyclase activity (750 [430] pmol cyclic adenosine monophosphate per milligram total protein 15 min before CPB compared with 540 [390] at the end of CPB, P = 0.0062, medians [interquartile range]) despite constant betaAR density. Differential activation along the betaAR signal transduction cascade localized the defect to the adenylyl cyclase moiety. Administration of long-term preoperative betaAR antagonists did not prevent acute CPB-induced myocardial betaAR dysfunction. CONCLUSIONS: These data indicate that the myocardial adenylyl cyclase response to betaAR agonists decreases acutely in adults during aortocoronary surgery requiring CPB, regardless of whether long-term preoperative betaAR antagonists are administered. The mechanism underlying acute betaAR dysfunction appears to be direct impairment of the adenylyl cyclase moiety. Similar increases in manganese-stimulated activity before and at the end of CPB show preserved adenylyl cyclase catalytic activity, suggesting that other mechanisms (such as decreased protein levels or altered isoform expression or function) may be responsible for decreased adenylyl cyclase function.

Adenylyl Cyclases↗
PubMed1998

Multiple potential regulatory elements in the 5' flanking region of the human alpha 1a-adrenergic receptor.

In spite of their critical importance in myocardial hypertrophy and benign prostatic hyperplasia, nothing is known about mechanisms underlying transcriptional regulation of alpha 1a-adrenergic receptors (alpha 1aARs). Therefore we cloned 6.2 kb of novel sequence upstream of the initiator ATG in the human alpha 1aAR gene. Sequence analysis reveals a TATA-less promoter, the presence of several initiator (Inr) consensus sequences, multiple GC rich regions consistent with Sp-1 binding, and consensus sequences for AP-1 and AP-2 as well as putative cis transcriptional regulatory elements for binding of CREB (cyclic-AMP response element binding protein), glucocorticoids, estrogen, and insulin. Compared to the alpha 1bAR, the alpha 1aAR has several more cis regulatory elements, suggesting more complex regulation. The importance of alpha 1aARs in human disease makes it imperative to determine mechanisms underlying transcription and ultimately expression of this receptor. These studies can now be undertaken with the availability of human alpha 1aAR 5'-flanking and 5'-untranslated sequence.

5' Untranslated Regions↗
PubMed1998

Human substance P receptor expressed in Sf9 cells couples with multiple endogenous G proteins.

To identify the G proteins involved in the function of human substance P receptor (hSPR), the receptor was expressed in Sf9 cells using the baculovirus expression system. Maximal hSPR expression was up to 65 pmol/mg membrane protein. The following data indicated that hSPR in Sf9 membranes is coupled to endogenous G proteins: 1) binding of agonist radioligand [125I]BHSP to the receptor was sensitive to guanine nucleotides; and 2) stimulation of the receptor increased [35S]GTPgammaS binding. The hSPR-associated G proteins were identified by photoaffinity labeling with [alpha-32P]-azidoanilido GTP ([alpha-32P]AAGTP), followed by immunoprecipitation of the labeled G proteins with antibodies specific for various Galpha-subunits. These experiments showed that stimulation of hSPR in Sf9 membranes activated multiple endogenous G proteins including Galpha(o), Galpha(q/11), and Galpha(s). While hSPR's ability to associate with Gq/11 is well-documented, the present study provides the first evidence of hSPR's potential to activate Galpha(o) and Galpha(s).

Animals↗
PubMed1997

Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region.

We recently cloned cDNAs encoding three subtypes of human alpha1-adrenergic receptors (alpha1ARs), alpha1a, alpha1b, and alpha1d (Schwinn, D. A., Johnston, G. L., Page, S. O., Mosley, M. J., Wilson, K. H., Worman, N. P., Campbell, S., Fidock, M. D., Furness, L. M., Parry-Smith, D. J., Peter, B., and Bailey, D. S. (1995) J. Pharmacol. Exp. Ther. 272, 134-142) and demonstrated predominance of alpha1aARs in many human tissues (Price, D. T., Lefkowitz, R. J., Caron, M. G., Berkowitz, D., and Schwinn, D. A. (1994) Mol. Pharmacol. 45, 171-175). Several lines of evidence indicate that alpha1aARs are important in clinical diseases such as myocardial hypertrophy and benign prostatic hyperplasia. Therefore, we initiated studies to understand mechanisms underlying regulation of alpha1aAR gene transcription. A genomic clone containing 6.2 kb of 5'-untranslated region of the human alpha1aAR gene was recently isolated. Ribonuclease protection and primer extension assays indicate that alpha1aAR gene transcription occurs at multiple initiation sites with the major site located 696 base pairs upstream of the ATG, where a classic initiator sequence is located. Transfection of luciferase reporter constructs containing varying amounts of 5'-untranslated region into human SK-N-MC neuroblastoma cells indicate that a region extending 125 base pairs upstream from the main transcription initiation site contains full alpha1aAR promoter activity. Furthermore, distinct activator and suppressor elements lie 2-3 and 3-5 kilobase pairs upstream, respectively. Although the alpha1aAR promoter contains neither TATA or CAAT elements, gel shift mobility assays targeting three GC boxes immediately upstream of the main transcription initiation site confirm binding of Sp1. Activity of the alpha1aAR promoter is cell-specific, demonstrating highest activity in cells endogenously expressing alpha1aARs. The human alpha1aAR gene also contains several cis regulatory elements, including several insulin and cAMP response elements. Consistent with these observations, we provide the first evidence that treatment of SK-N-MC cells with insulin and cAMP elevating agents leads to an increase in alpha1aAR expression. In conclusion, these data represent the first characterization of the alpha1aAR gene; our findings should facilitate further studies designed to understand mechanisms regulating alpha1AR subtype-specific expression in healthy and diseased human tissue.

Cloning, Molecular↗
PubMed1996

Human G(alpha q): cDNA and tissue distribution.

G(alpha q), a member of the Gq family of heterotrimeric G proteins, transduces signals from several G protein-coupled receptors that stimulate membrane phosphoinositide hydrolysis. In order to further define the role of G(alpha q) in the function of G protein-coupled receptors, we have cloned the cDNA encoding human G(alpha q) from a prostate cDNA library. Human G(alpha q) exhibits high homology with its mouse homolog - 94% similarity at the nucleotide level, and 99% similarity at the amino acid level. Northern hybridization data indicate high expression of G(alpha q) mRNA in organs of the human reproductive system including ovary, prostate, and testis.

Amino Acid Sequence↗
PubMed1995

Immunoaffinity purification of epitope-tagged human beta 2-adrenergic receptor to homogeneity.

To obtain large quantities of pure human beta 2-adrenergic receptor (beta 2-AR) needed for structural studies, an efficient method for beta 2-AR purification was developed using a recombinant receptor with an eight amino acid epitope at its C-terminus. This epitope is recognized by KT3-monoclonal antibody. The epitope tagged beta 2-AR was expressed in Sf9 cells with a specific activity of 5-20 pmol/mg of membrane protein. The epitope-tagged and wild-type receptors had identical ligand binding properties. The tagged receptor was solubilized using dodecyl-beta-maltoside with a quantitative yield. Solubilized epitope-tagged receptors were partially purified by KT3-mAb immunoaffinity in 60-70% yield. Further purification of the receptors on an alprenolol-affinity column resulted in a homogenous preparation with an overall yield of > 30%. The purified receptor was concentrated to > 1 mg/ml without loss of ligand binding activity.

Alprenolol↗
PubMed1995

Cardiac muscarinic potassium channel activity is attenuated by inhibitors of G beta gamma.

The cardiac muscarinic potassium channel (IK.ACh) is activated by a G protein upon receptor stimulation with acetylcholine. The G protein subunit responsible for activation (G alpha versus G beta gamma) has been disputed. We used G beta gamma inhibitors derived from the beta-adrenergic kinase 1 (beta ARK1) to assess the relative importance of G beta gamma in IK.ACh activation. In rabbit atrial myocytes, IK.ACh had a conductance of 49 +/- 6.2 pS. In inside-out patches, the mean open time was 1.60 +/- 0.57 ms, mean time constant (tau o) was 1.59 +/- 0.53 ms, and mean closed time was 3.02 +/- 1.35 ms (n = 38). beta ARK1 is a G beta gamma-sensitive enzyme that interacts with G beta gamma through a defined sequence near its carboxyl terminus. A 28-amino-acid peptide derived from the carboxyl terminus of beta ARK1 (peptide G) increased the closed time to 10.04 ms (P < .001) and decreased opening probability (NPo) by 71% (P < .001). Fusion proteins containing the entire carboxyl terminus of beta ARK1, glutathione S-transferase beta ARK1ct and hexahistidine beta ARK1ct, decreased NPo by 67% (P = .03) and 48% (P = .009), respectively. They also both significantly increased the closed time. None of the inhibitors affected mean open time or channel amplitude. A control peptide derived from a neighboring region of beta ARK1 had no significant effect on IK.ACh activity. These results provide further evidence for the role of G beta gamma in the activation of IK.ACh.

Animals↗
PubMed1994

A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.

An aromatic residue, tyrosine 326 in the prototypical human beta 2-adrenergic receptor, exists in a highly conserved sequence motif in virtually all members of the G protein-coupled receptor family. The potential role of this conserved aromatic amino acid residue in the cellular processes of sequestration (a rapid internalization of the surface receptor) and down-regulation (a slower loss of total cellular receptors) associated with agonist-mediated desensitization of the beta 2-adrenergic receptor was assessed by replacing tyrosine residue 326 with an alanine residue (beta 2AR-Y326A). This mutation completely abolishes agonist-mediated receptor sequestration without affecting the ability of the receptor to activate maximally adenylyl cyclase, to undergo rapid desensitization, and to down-regulate in response to agonist. The only other major change associated with the mutated receptor is a complete loss of the ability to resensitize following rapid desensitization. These results imply that this tyrosine residue, which is part of a highly conserved sequence motif in G protein-coupled receptors, may be responsible for their agonist-mediated sequestration and that sequestration and down-regulation of the receptor are dissociable phenomena. The lack of resensitization in the sequestration-defective beta 2-adrenergic receptor mutant strongly suggests that the sequestration pathway is an important mechanism by which cells re-establish the normal responsiveness of G protein-coupled receptors following the removal of agonist.

Alanine↗
PubMed1993

The substance P receptor, which couples to Gq/11, is a substrate of beta-adrenergic receptor kinase 1 and 2.

The agonist-occupied forms of several G-protein-coupled receptors that modulate the activity of adenylycyclase via Gs (e.g. beta 2-adrenergic) or Gi (e.g. alpha 2-adrenergic and cardiac muscarinic) are phosphorylated by beta-adrenergic receptor kinases (beta ARK 1 and beta ARK 2). beta ARK-catalyzed phosphorylation of these receptors appears to correlate with their agonist-induced desensitization. The possibility that beta ARK isozymes may also be involved in the desensitization of other G-protein-coupled receptors such as those mediating phosphoinositide (PI) hydrolysis was tested by determining the phosphorylation of the substance P receptor (SPR), which is coupled to PI hydrolysis in numerous tissues. Rat SPR was expressed in Sf9 cells, partially purified, and reconstituted in phospholipid vesicles. The reconstituted SPR bound the SPR agonist substance P, 125I-labeled with Bolton-Hunter reagent, with low affinity. However, addition of purified Gq/11 to the reconstituted SPR resulted in the conversion of all the receptors to a high affinity state, suggesting that SPR couples to Gq/11. Phosphorylation of the reconstituted SPR with purified beta ARK 1 or 2 in the absence and presence of substance P (SP) was then studied. In the presence of 100 microM SP, both kinases promoted phosphorylation of the receptor to a stoichiometry of 9 +/- 2 mol of phosphate/mol of receptor. However, no phosphorylation of the receptor could be detected in the absence of agonist. Agonist-induced phosphorylation of the receptor was blocked by coincubation with the SPR antagonist spantide. These results show that beta ARK isozymes may regulate the function of both adenylylcyclase as well as PI-coupled receptors, and suggest a role for beta ARK isozymes in SPR signal transduction.

Animals↗
PubMed1992

Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family.

Homologous or agonist-specific desensitization of beta 2-adrenergic receptors (beta 2AR) is mediated by the beta-adrenergic receptor kinase (beta ARK) which specifically phosphorylates the agonist-occupied form of the receptor. However, the capacity of beta ARK-phosphorylated beta 2AR to stimulate Gs in a reconstituted system is only minimally impaired. Recently, a protein termed beta-arrestin, was cloned from a bovine brain cDNA library and found to quench phosphorylated beta 2AR-coupling to Gs. Utilizing a low stringency hybridization technique to screen a rat brain cDNA library, we have now isolated cDNA clones representing two distinct beta-arrestin-like genes. One of the cDNAs is the rat homolog of bovine beta-arrestin (beta-arrestin1). In addition, we have isolated a cDNA clone encoding a novel, beta-arrestin-related protein which we have termed beta-arrestin2. Overall, beta-arrestin2 exhibits 78% amino acid identity with beta-arrestin1. The primary structure of these proteins delineates a family of proteins that regulates receptor coupling to G proteins. The capacity of purified beta-arrestin1, beta-arrestin2, and arrestin to inhibit the coupling of phosphorylated receptors to their respective G proteins were assessed in a reconstituted beta 2AR-Gs system and in a reconstituted rhodopsin-GT system. beta-Arrestin2 was equipotent to beta-arrestin1 and specifically inhibited beta 2AR function. Conversely, arrestin inhibited rhodopsin coupling to GT, whereas beta-arrestin1 and beta-arrestin2 were at least 20-fold less potent in this system. beta-Arrestin1 and beta-arrestin2 are predominantly localized in neuronal tissues and in the spleen. However, low mRNA levels can be detected in most peripheral tissues. In the central nervous system, beta-arrestin2 appears to be even more abundant than beta-arrestin1. Immunohistochemical analysis of the tissue distribution of beta-arrestin1 and beta-arrestin2 in rat brain shows extensive, but heterogenous, neuronal labeling of the two proteins. They are found in several neuronal pathways suggesting that they have relatively broad receptor specificity regulating many G protein-coupled receptors. Furthermore, immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors.

Amino Acid Sequence↗