Functional domains of the C-terminus of the rat angiotensin AT1A receptor

Balmforth, Anthony J.; Lee, Alison J.; Bajaj, B. P. S.; Dickinson, Catherine J; Warburton, Philip; Ball, Stephen G.

doi:10.1016/0922-4106(95)90135-3

Cited by 28 publications

(26 citation statements)

References 26 publications

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“…However, most recently Oppermann et al (1996) have argued that GRK mediated phosphorylation plays the dominant role in such regulation. In a previous study we established that consensus sites for PKC, located in the carboxyl-terminal region of the AT 1A , were actively involved in receptor uncoupling (Balmforth et al, 1995). The results of the present study support our earlier ®ndings and demonstrate directly a pivotal role for PKC-induced AT 1 receptor phosphorylation in desensitization at agonist concentrations of AII likely to occur under physiological circumstances.…”

Section: Discussionsupporting

confidence: 91%

“…There is substantial indirect evidence for this mechanism (Brock et al, 1985;Pfeilschifter, 1986;Pfeilschifter et al, 1989;Abdellatif et al, 1991;Ochsner et al, 1993;Tang et al, 1995) and that this leads to an uncoupling of the AII receptors from their G-proteins (Pfeilschifter & Bauer, 1987;Abdellatif et al, 1991). Furthermore, using a truncated AT 1A receptor lacking 41 amino acids from the C-terminus which included the three putative protein kinase C phosphorylation sites, we recently demonstrated that at least one of these sites was actively involved in the uncoupling of the receptor by protein kinase C (Balmforth et al, 1995).…”

Section: Introductionmentioning

confidence: 82%

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Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor

Balmforth

Shepherd

Warburton

et al. 1997

British J Pharmacology

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1 The role of protein kinase C (PKC) in the mechanism underlying rapid agonist-induced desensitization of angiotensin AT 1 receptors remains unresolved. A major problem has been to isolate these receptors in a su ciently puri®ed form to allow study of their phosphorylation state. 2 A cleavable (His) 6 a nity tag was introduced into the N-terminus of the recombinant AT 1A receptor and stably expressed in human embryonic kidney cells. This a nity tag allowed rapid isolation, puri®cation and determination of the phosphorylation state of the AT 1A receptor. Using these cells, we determined the role of PKC in both agonist-induced receptor phosphorylation and desensitization under identical conditions. 3 Agonist-induced phosphorylation of the AT 1A receptor was observed at both low and high concentrations of angiotensin II (AII). Preincubation of cells with Ro-31-8220 (a PKC speci®c inhibitor) revealed that at low concentrations of AII (1 nM), PKC appeared to be the main kinase involved in receptor phosphorylation. In contrast, at high concentrations of AII (100 nM), although PKC-mediated phosphorylation of the receptor was observed, this was overshadowed by a second kinase. 4 In preliminary desensitization studies we observed that at a low concentration of AII, preincubation with Ro-31-8220 attenuated desensitization, whilst at high concentrations of AII (100 nM) it had little or no e ect on the level of desensitization observed.5 These data directly demonstrate an association between PKC-induced receptor phosphorylation and desensitization at low concentrations of AII. Since circulating concentrations of AII are in the picomolar range, we propose that PKC is the physiologically relevant mediator of AT 1 receptor desensitization.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 82%

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor

Balmforth

Shepherd

Warburton

et al. 1997

British J Pharmacology

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“…In this respect, one may question which phosphorylated site of the receptor should be responsible for desensitization. A predominant role for phosphorylation of the intracellular C-terminal tail has been frequently invoked in these mechanisms of desensitization [8][9][10][11][12]. The strongest experimental evidence for such a role of the C-terminal tail is the lack of rapid desensitization of receptors which C-terminal tail is truncated [7,9,12,20].…”

Section: Resultsmentioning

confidence: 99%

“…This phosphorylation may be consecutive to binding of the ligand to the receptor or to activation of protein kinase by second messengers [7][8][9][10][11]. The role of protein kinase A activation by cAMP on desensitization has been well demonstrated for adenylyl cyclase coupled receptor.…”

Section: Introductionmentioning

confidence: 99%

Role of protein kinase C and carboxyl‐terminal region in acute desensitization of vasopressin V1a receptor

et al. 1997

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The role of protein kinase C activation and carboxylterminal region in rapid desensitization of the vasopressin Via receptor was investigated in Xenopus oocytes. Preincubation of the oocytes with vasopressin or with the diacylglycerol analog l-oleoyl-2-acetyl-sn-glycerol (OAG), or direct injection of active protein kinase C, all blunted the calcium response of the Via receptor. Truncation of the 51 terminal amino acids (S374STOP) modified neither the intracellular calcium response to vasopressin nor its desensitization by vasopressin or OAG. These data suggest that desensitization of the Via receptor is mediated by PKC activation and that its carboxyl-terminal domain is not required for signal transduction and rapid desensitization.

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“…However, mutations in the corresponding motif in the angiotensin AT 1 receptor did not affect ligand-induced internalization (7)(8)(9). On the other hand, the Cterminal cytoplasmic domain of AT 1 was found to be important for internalization (8,10,11), particularly residues L316, Y319 (6), T332, S335, T336 and L337 (7). Furthermore, residues 215-220 at the N-terminal portion of the third intracellular loop, but not other segments of this loop, were found to be important for AT 1 endocytosis (12).…”

Section: Introductionmentioning

confidence: 99%

Ligand-induced endocytosis and nuclear localization of angiotensin II receptors expressed in CHO cells

Merjan

Kanashiro

Krieger

et al. 2001

Braz J Med Biol Res

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A construct (AT1R-NF) containing a "Flag" sequence added to the Nterminus of the rat AT 1 receptor was stably expressed in Chinese hamster ovary cells and quantified in the cell membrane by confocal microscopy after reaction with a fluorescein-labeled anti-Flag monoclonal antibody. Angiotensin II bound to AT1R-NF and induced endocytosis with a half-time of 2 min. After 60-90 min, fluorescence accumulated around the cell nucleus, suggesting migration of the ligand-receptor complex to the nuclear membrane. Angiotensin antagonists also induced endocytosis, suggesting that a common step in the transduction signal mechanism occurring after ligand binding may be responsible for the ligand-receptor complex internalization. Correspondence

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Functional domains of the C-terminus of the rat angiotensin AT1A receptor

Cited by 28 publications

References 26 publications

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor

Role of protein kinase C and carboxyl‐terminal region in acute desensitization of vasopressin V1a receptor

Ligand-induced endocytosis and nuclear localization of angiotensin II receptors expressed in CHO cells

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Functional domains of the C-terminus of the rat angiotensin AT1A receptor

Cited by 28 publications

References 26 publications

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT1A receptor

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT1A receptor

Role of protein kinase C and carboxyl‐terminal region in acute desensitization of vasopressin V1a receptor

Ligand-induced endocytosis and nuclear localization of angiotensin II receptors expressed in CHO cells

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Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor

Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT_1A receptor