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Insulin inhibits cardiac contractility by inducing a Gi-biased ?2-adrenergic signaling in hearts.

ABSTRACT: Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and ?2-adrenergic receptor (?2AR) in the heart. The IR/?2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the ?2AR, which promotes ?2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of ?2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated ?2AR-Gi signaling effectively attenuates cAMP/PKA activity after ?-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair ?AR-regulated cardiac contractility. This ?2AR-dependent IR and ?AR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.

SUBMITTER: Fu Q

PROVIDER: S-EPMC4113065 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.

Fu Qin Q Xu Bing B Liu Yongming Y Parikh Dippal D Li Jing J Li Ying Y Zhang Yuan Y Riehle Christian C Zhu Yi Y Rawlings Tenley T Shi Qian Q Clark Richard B RB Chen Xiongwen X Abel E Dale ED Xiang Yang K YK

Diabetes 20140327 8

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) a ...[more]

PMID: 24677713

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Project description:AimsTo determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe reported previously that transgenic mice with cardiac-restricted ?1A-AR overexpression (?1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G?q/11-coupled receptor in hypertrophy.MethodsContractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from ?1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after ?1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.ResultsHypercontractility without hypertrophy with ?1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, ?1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its G?q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the ?1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective ?1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without ?1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.ConclusionsWe report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

Dataset Information

Insulin inhibits cardiac contractility by inducing a Gi-biased ?2-adrenergic signaling in hearts.

Publications

Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.

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