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Attenuation of early restenosis after percutaneous coronary intervention (PCI) is important for the successful treatment of coronary artery disease. Some clinical studies have shown that hypertension is a risk factor for early restenosis after PCI. These findings suggest that [[alpha].sub.1]-adrenergic receptors ([[alpha].sub.1]-ARs) may facilitate restenosis after PCI because of [[alpha].sub.1]-AR's remarkable contribution to the onset of hypertension. In this study, we examined the neointimal formation after vascular injury in the femoral artery of [[alpha].sub.1A]-knockout ([[alpha].sub.1A]-KO), [[alpha].sub.1B]-KO, [[alpha].sub.1D]-KO, [[alpha].sub.1A]-/[[alpha].sub.1B]-AR double-KO ([[alpha].sub.1AB]-KO), and wild-type mice to investigate the functional role of each [[alpha].sub.1]-AR subtype in neointimal formation, which is known to promote restenosis. Neointimal formation 4 wk after wire injury was significantly (P < 0.05) smaller in [[alpha].sub.1AB]-KO mice than in any other group of mice, while blood pressures were not altered in any of the groups of mice after wire injury compared with those before it. These results suggest that lack of both [[alpha].sub.1A]- and [[alpha].sub.1B]-ARs could be necessary to inhibit neointimal formation in the mouse femoral artery. [[alpha].sub.1]-adrenergic receptor: vascular injury; smooth muscle cell: femoral artery of mouse; wire injury doi:10.1152/ajpheart.00626.2006

In response to various pathological stresses, the heart undergoes a pathological remodeling process that is associated with cardiomyocyte hypertrophy. Because cardiac hypertrophy can progress to heart failure, a major cause of lethality worldwide, the intracellular signaling pathways that control cardiomyocyte growth have been the subject of intensive investigation. It has been known for more than a decade that the small molecular weight GTPase RhoA is involved in the signaling pathways leading to cardiomyocyte hypertrophy. Although some of the hypertrophic pathways activated by RhoA have now been identified, the identity of the exchange factors that modulate its activity in cardiomyocytes is currently unknown. In this study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor activity, is critical for activating RhoA and transducing hypertrophic signals downstream of [alpha]1-adrenergic receptors (ARs). In particular, our results indicate that suppression of AKAP-Lbc expression by infecting rat neonatal ventricular cardiomyocytes with lentiviruses encoding AKAP-Lbc-specific short hairpin RNAs strongly reduces both [alpha]1-AR-mediated RhoA activation and hypertrophic responses. Interestingly, [alpha]1-ARs promote AKAP-Lbc activation via a pathway that requires the subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as the first Rho-guanine nucleotide exchange factor (GEF) involved in the signaling pathways leading to cardiomyocytes hypertrophy. cardiac hypertrophy | Rho GTPase | G protein-coupled receptor

The idea that a receptor can produce signalling without agonist intervention and that several antagonists can be 'active' in repressing such spontaneous activity is contained in the concept of ligand-induced conformational changes. Yet, this idea was neglected by pharmacologists for many years. In this article, we review the events that brought inverse agonism and constitutive activity to general attention and made this phenomenon a topic of current research. We also suggest a classification of antagonists based on the cooperativity that links their primary site of interaction with other functional domains of the receptor.

Gene deletion of dopamine [beta]-hydroxylase and [[alpha].sub.1]-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling. Am J Physiol Heart Circ Physiol 287: H2106-H2114, 2004. First published July 1, 2004; doi:10.1152/ajpheart.00290.2004.--In vitro studies have shown that stimulation of [[alpha].sub.1]-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine [beta]-hydroxylase (DB[H.sup.-/-])] or deficient in [[alpha].sub.1]-AR subtypes expressed in murine carotid ([[alpha].sub.1B]-[AR.sup.-/-] and [[alpha].sub.1D]-[AR.sup.-/-]) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DB[H.sup.-/-] and [[alpha].sub.1B]-[AR.sup.-/-] mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DB[H.sup.-/-]) or normal ([[alpha].sub.1B]-[AR.sup.-/-]). In contrast, in [[alpha].sub.1D]-[AR.sup.-/-] mice, increases in lumen area. circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DB[H.sup.-/-] mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by [[alpha].sub.1B]-ARs in mouse carotid and contribute to hypertrophic growth alter vascular injury. adrenergic receptors; knockout; smooth muscle; adventitia; growth; injury

Research has been conducted on the co- and posttranslational modification of the alpha (sub)1B-adrenergic receptor. The steps involved in the receptor maturation and the conditions optimized for the receptor overexpression have been investigate and the results are reported.

In this study, a quantitative approach was used to investigate the role of D142, which belongs to the highly conserved E/DRY sequence, in the activation process of the [[Alpha].sub.1B]-adrenergic receptor ([[Alpha].sub.1B]-AR). Experimental and computer-simulated mutagenesis were performed by substituting all possible natural amino acids at the D142 site. The resulting congeneric set of proteins together with the finding that all the receptor mutants show various levels of constitutive (agonist-independent) activity enabled us to quantitatively analyze the relationships between structural/dynamic features and the extent of constitutive activity. Our results suggest that the hydrophobic/hydrophilic character of D142, which could be regulated by protonation/deprotonation of this residue, is an important modulator of the transition between the inactive (R) and active ([R.sup.*]) state of the [[Alpha].sub.1B]-AR. Our study represents an example of quantitative structure-activity relationship analysis of the activation process of a G protein-coupled receptor.

Several G protein-coupled receptors promote the protein kinase A (PKA)-mediated phosphorylation of Na-K-adenosinetriphosphatase (Na-K-ATPase) in different cell systems. The phosphorylation inducing receptors are adrenergic, dopaminergic and muscarinic cholinergic receptor subspecies. Stimulation of the receptors induces phosphorylation of the wild-type and PKC phosphorylation site-deficient Na-K-ATPase. However, the Na-K-ATPase alpha subunit, lacking the PKA phosphorylation site, does not undergo phosphorylation.

Adrenoceptors are prototypic members of the superfamily of seven transmembrane domain, G protein-coupled receptors. Study of the properties of several mutationally activated adrenoceptors is deepening understanding of the normal functioning of this ubiquitous class of receptors. The new findings suggest an expansion of the classical ternary complex model of receptor action to include an explicit isomerization of the receptors from an inactive to an active state which couples to the G protein ('allosteric ternary complex model'). This isomerization involves conformational changes which may occur spontaneously, or be induced by agonists or appropriate mutations which abrogate the normal 'constraining' function of the receptor, allowing it to 'relax' into the active conformation. Robert Lefkowitz and colleagues discuss the physiological and pathophysiological implications of these new insights into regulation of receptor activity.

The actions of many hormones and neurotransmitters are mediated by the members of a superfamily of receptors coupled to heterotrimeric guanine nucleotide - binding proteins (G proteins). These receptors are characterized by a highly conserved topographical arrangement in which seven transmembrane domains are connected by intracellular and extracellular loops. The interaction between these receptors and G proteins is mediated in large part by the third intracellular loop of the receptor. Coexpression of the third intracellular loop of the [alpha.sub.1B]-adrenergic receptor with its parent receptor inhibited receptor-mediated activation of phospholipase C. The inhibition extended to the closely related [alpha.sub.c]-adrenergic receptor subtype, but not the phospholipase C - coupled M1 muscarinic acetylcholine receptor nor the adenylate cyclase - coupled [D.sub.1A] dopamine receptor. These results suggest that the receptor - G protein interface may represent a target for receptor antagonist drugs., The binding of agonists to G protein-coupled receptors induces conformational changes in the receptor that promote formation of an agonist receptor-G protein ternary complex[1] that leads to G protein activation [...]