TY - JOUR
T1 - Roles of heterotrimeric GTP-binding proteins in the progression of heart failure
AU - Nishida, Motohiro
PY - 2011
Y1 - 2011
N2 - Heart failure is a major cause of death in developed countries, and the development of an epoch-making cure is desired from the viewpoint for improving the quality of life and reducing the medical cost of the patient. The importance of neurohumoral factors, such as angiotensin (Ang) II and catecholamine, for the progression of heart failure has been supported by a variety of evidence. These agonists stimulate seven transmembrane-spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have revealed that á subunit of Gq (Gαq) activates Ca2+-dependent hypertrophic signaling through diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6: TRPC3/6). In contrast, activation of Gα12 family proteins in cardiomyocytes confers pressure overload-induced cardiac fibrosis via stimulation of purinergic P2Y6 receptors induced by extracellular nucleotides released from cardiomyocytes. In fact, direct or indirect inhibition of TRPC3/6 or P2Y6 receptors attenuates pressure overload-induced cardiac dysfunction. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure.
AB - Heart failure is a major cause of death in developed countries, and the development of an epoch-making cure is desired from the viewpoint for improving the quality of life and reducing the medical cost of the patient. The importance of neurohumoral factors, such as angiotensin (Ang) II and catecholamine, for the progression of heart failure has been supported by a variety of evidence. These agonists stimulate seven transmembrane-spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have revealed that á subunit of Gq (Gαq) activates Ca2+-dependent hypertrophic signaling through diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6: TRPC3/6). In contrast, activation of Gα12 family proteins in cardiomyocytes confers pressure overload-induced cardiac fibrosis via stimulation of purinergic P2Y6 receptors induced by extracellular nucleotides released from cardiomyocytes. In fact, direct or indirect inhibition of TRPC3/6 or P2Y6 receptors attenuates pressure overload-induced cardiac dysfunction. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure.
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U2 - 10.1254/jphs.11R05CP
DO - 10.1254/jphs.11R05CP
M3 - Review article
C2 - 21821969
AN - SCOPUS:80052897166
VL - 117
SP - 1
EP - 5
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
SN - 1347-8613
IS - 1
ER -