The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

Jakob Lerche Hansen; Mark Aplin; Jonas Tind Hansen; Gitte Lund Christensen; Marie Mi Bonde; Mikael Schneider; Stig Haunsø; Hans H Schiffer; Ethan S Burstein; David M Weiner; Søren P Sheikh

doi:10.1016/j.ejphar.2008.05.010

The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

Jakob Lerche Hansen, Mark Aplin, Jonas Tind Hansen, Gitte Lund Christensen, Marie Mi Bonde, Mikael Schneider, Stig Haunsø, Hans H Schiffer, Ethan S Burstein, David M Weiner, Søren P Sheikh

Department of Neuroscience

22 Citations (Scopus)

Abstract

The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.

Original language	English
Journal	European Journal of Pharmacology
Volume	590
Issue number	1-3
Pages (from-to)	255-63
Number of pages	9
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2008.05.010
Publication status	Published - 2008

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Hansen, J. L., Aplin, M., Hansen, J. T., Christensen, G. L., Bonde, M. M., Schneider, M., Haunsø, S., Schiffer, H. H., Burstein, E. S., Weiner, D. M., & Sheikh, S. P. (2008). The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation. European Journal of Pharmacology, 590(1-3), 255-63. https://doi.org/10.1016/j.ejphar.2008.05.010

The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation. / Hansen, Jakob Lerche; Aplin, Mark; Hansen, Jonas Tind et al.

In: European Journal of Pharmacology, Vol. 590, No. 1-3, 2008, p. 255-63.

Research output: Contribution to journal › Journal article › Research › peer-review

Hansen, JL, Aplin, M, Hansen, JT, Christensen, GL, Bonde, MM, Schneider, M, Haunsø, S, Schiffer, HH, Burstein, ES, Weiner, DM & Sheikh, SP 2008, 'The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation', European Journal of Pharmacology, vol. 590, no. 1-3, pp. 255-63. https://doi.org/10.1016/j.ejphar.2008.05.010

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title = "The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation",

abstract = "The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.",

author = "Hansen, {Jakob Lerche} and Mark Aplin and Hansen, {Jonas Tind} and Christensen, {Gitte Lund} and Bonde, {Marie Mi} and Mikael Schneider and Stig Hauns{\o} and Schiffer, {Hans H} and Burstein, {Ethan S} and Weiner, {David M} and Sheikh, {S{\o}ren P}",

note = "Keywords: Animals; COS Cells; Cell Proliferation; Cercopithecus aethiops; Drug Inverse Agonism; Enzyme Activation; GTP-Binding Proteins; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NIH 3T3 Cells; Receptor, Angiotensin, Type 1; Signal Transduction",

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AU - Hansen, Jakob Lerche

AU - Aplin, Mark

AU - Hansen, Jonas Tind

AU - Christensen, Gitte Lund

AU - Bonde, Marie Mi

AU - Schneider, Mikael

AU - Haunsø, Stig

AU - Schiffer, Hans H

AU - Burstein, Ethan S

AU - Weiner, David M

AU - Sheikh, Søren P

N1 - Keywords: Animals; COS Cells; Cell Proliferation; Cercopithecus aethiops; Drug Inverse Agonism; Enzyme Activation; GTP-Binding Proteins; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NIH 3T3 Cells; Receptor, Angiotensin, Type 1; Signal Transduction

PY - 2008

Y1 - 2008

N2 - The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.

AB - The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.

U2 - 10.1016/j.ejphar.2008.05.010

DO - 10.1016/j.ejphar.2008.05.010

M3 - Journal article

C2 - 18565507

SN - 0014-2999

VL - 590

SP - 255

EP - 263

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-3

ER -

The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

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