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Balakumar P.,Rajendra Institute of Technology and science RITS | Mahadevan N.,Rajendra Institute of Technology and science RITS
Biomedicine and Aging Pathology | Year: 2011

G protein-coupled receptors (GPCRs) at plasma membrane transduce signals in response to binding of ligands, involving heterotrimeric GTP binding proteins (G proteins). Several endogenous ligands such as epinephrine, norepinephrine, dopamine, endothelin, vasopressin, adenosine, bradykinin, glucagon, and many hormones have been recognized as ligands for GPCRs. The binding of a ligand to GPCR causes allosteric changes in the receptor, resulting in the formation of high affinity ligand-GPCR-G protein complex, which initiates the intracellular signal transduction by modulating numerous effector enzymes and ion channels. The termination of GPCR-mediated signaling takes place by an event of desensitization, which occurs as a result of phosphorylation of the receptor by GPCR kinase and subsequent recruitment of β-arrestin, a multifunctional adapter protein. The β-arrestin, by uncoupling G proteins from the receptor, efficiently terminates GPCRs signal transduction. Interestingly, recent studies revealed that β-arrestin can also turn on some GPCR signaling in a mechanism independently to G protein involvements. The chronic stimulation of certain GPCRs results in various cardiovascular disorders including hypertension, cardiac hypertrophy and progression to heart failure. Understanding the key functional regulation of GPCR-signaling is considerably important in the fundamental process of drug discovery in the area of cardiovascular sciences. In light of this view, the present review critically discussed GPCR-mediated cellular signaling cascade. Moreover, potential molecular target sites pertinent to cardiac GPCR-signaling to develop novel cardiovascular pharmacological interventions have been delineated. © 2011 Elsevier Masson SAS. All rights reserved.

Garg M.,Rajendra Institute of Technology and science RITS | Khanna D.,Rajendra Institute of Technology and science RITS
Therapeutic Advances in Cardiovascular Disease | Year: 2014

High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders. © 2014 The Author(s).

PubMed | Rajendra Institute of Technology and science RITS
Type: Journal Article | Journal: Cellular signalling | Year: 2011

Diabetes mellitus-associated ischemic heart disease is a major public burden in industrialized countries. Reperfusion to a previously ischemic myocardium is obligatory to reinstate its function prior to irreversible damage. However, reperfusion is considered a double-edged sword as reperfusion per se could augment myocardial ischemic damage, known as myocardial ischemia-reperfusion (I/R) injury. The brief and repeated cycles of I/R given before a sustained ischemia and reperfusion are represented as ischemic preconditioning, which protects the heart from lethal I/R injury. Few studies have demonstrated preconditioning-mediated cardioprotection in the diabetic heart. In contrast, considerable number of studies suggests that myocardial defensive effects of preconditioning are abolished in the presence of chronic diabetes mellitus that raised questions over preconditioning effects in the diabetic heart. It is evidenced that chronic diabetes mellitus-associated deficit in survival pathways, impaired function of mito-K(ATP) channels, MPTP opening and high oxidative stress play key roles in paradoxically suppressed cardioprotective effects of preconditioning in the diabetic heart. These controversial results open up a new area of research to identify potential mechanisms influencing disparities on preconditioning effects in diabetic hearts. In this review, we discussed first the discrepancies on the modulatory role of diabetes mellitus in I/R-induced myocardial injury. Following this, we addressed whether preconditioning could protect the diabetic heart against I/R-induced myocardial injury. Moreover, potential mechanisms pertaining to the attenuated cardioprotective effects of preconditioning in the diabetic heart have been delineated. These are important to be understood for better exploitation of preconditioning strategies in limiting I/R-induced myocardial injury in the diabetic heart.

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