Bruce B Lerman   Professor of Medicine

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Dysregulation of G protein Signaling in Idiopathic Ventricular Tachycardia. Our laboratory studies the regulation of proteins (G proteins) that couple cell surface receptors to intracellular cAMP and their role in medicating adrenergically-dependent ventricular tachycardia. cAMP regulates phosphorylation and permeation of ion channels, which can result in intracellular calcium overload that triggers malignant arrhythmias in patients without structural heart disease. Our laboratory has identified cardiac mutations in several regulatory G proteins, which are thought to be responsible for this form of tachycardia. Mutations in these G proteins couple to either the β-adrenergic receptor of the muscarinic cholinergic receptor, and are of somatic origin, the first to be demonstrated in the heart. Transfection experiments show that these mutations increase intracellular cAMP. Our biochemical analyses has further shown that the identified mutations in the inhibitory G protein (Gαi2) impair binding of GTP, altering activation kinetics, whereas the mutations in the stimulatory G protein (Gs) cause constitutive activation, impairing hydrolysis of GTP.


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