Identification of amino acid residues of rat angiotensin II receptor for ligand binding by site directed mutagenesis

Yamano, Yoshiaki; Ohyama, Kenji; Chaki, Shigeyuki; Guo, Deng‐Fu; Inagami, Tadashi

doi:10.1016/0006-291x(92)90461-s

Cited by 140 publications

(67 citation statements)

References 14 publications

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“…The current view is that AngII binding to the AT 1 receptor involves two salt bridges, between the a-carboxyl group of AngII and Lys 199 of AT 1 receptor and between the guanidinium group of Arg-2 in AngII and Asp 281 in the receptor (Yamano et al, 1992;Feng et al, 1995;Noda et al, 1995a;Miura et al, 2003a (Feng et al, 1995;Boucard et al, 2000). Arg 23 in N terminus of AT 1 receptor may be essential for binding AngII (Santos et al, 2004a).…”

Section: A Structure-functionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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Section: A Structure-functionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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“…The HA-tagged AT1 receptor is functional and routinely used to study angiotensin II signal transduction pathways (39,40). The data presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

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“…For instance, Asn is replaced with Ala, which has a similar size but cannot form a hydrogen bond (H-bond). The Lys side chain is replaced with Gln, which has a similar size but cannot form a salt bridge, as described in previous mutagenesis studies (Yamano et al, 1992;Ji et al, 1994Ji et al, , 1995Schambye et al, 1994;Noda et al, 1995;Gosselin et al, 2000;Takezako et al, 2004;BaleanuGogonea and Karnik, 2006;Tuccinardi et al, 2006). To express the AT1R protein, 10 mg of purified plasmid DNA per 10 7 cells was used in the transfection.…”

Section: Introductionmentioning

confidence: 99%

Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

et al. 2015

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Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109 TM3 , Phe182 ECL2 , Gln257 TM6 , Tyr292 TM7 , and Asn295 TM7 ) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108 TM3 , Ser109 TM3 , Ala163 TM4 , Phe182 ECL2 , Lys199 TM5 , Tyr292 TM7 , and Asn295 TM7 ), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R.

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Identification of amino acid residues of rat angiotensin II receptor for ligand binding by site directed mutagenesis

Cited by 140 publications

References 14 publications

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

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