Phosphoinositide 3-Kinase Isoforms Selectively Couple Receptors to Vascular L-Type Ca
            <sup>2+</sup>
            Channels

Macrez, Nathalie; Mironneau, C.; Carricaburu, Valérie; Quignard, Jean-François; Бабич, А. А.; Czupalla, Cornelia; Nürnberg, Bernd; Mironneau, Jean

doi:10.1161/hh2001.097864

Cited by 88 publications

(82 citation statements)

References 35 publications

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“…The precise mechanism(s) by which vascular smooth muscle PI3K might promote contraction is still unclear but could include antagonism of cyclic nucleotide signaling pathways (Komalavilas et al, 2001), interactions with protein kinase C (Su et al, 2004), or regulation of voltage-gated calcium channels (Macrez et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Budzyn

Marley²,

Sobey³

2005

J Pharmacol Exp Ther

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Phosphatidylinositol 3-kinase (PI3K) can activate endothelial nitric oxide synthase (eNOS), leading to production of the vasodilator NO. In contrast, vascular smooth muscle (VSM) PI3K may partially mediate vascular contraction, particularly during hypertension. We tested whether endothelial and VSM PI3K may have opposing functional roles in regulating vascular contraction. Secondly, we tested whether the procontractile protein rho-kinase can suppress endothelial PI3K/eNOS activity in intact arteries, thus contributing to vasoconstriction by G protein-coupled receptor (GPCR) agonists. We studied contractile responses to the GPCR agonist phenylephrine, and the receptor-independent vasoconstrictor KCl, in aortic rings from Sprague-Dawley rats. In endothelium-intact rings, the PI3K inhibitor wortmannin (0.1 M) markedly augmented responses to phenylephrine (P Ͻ 0.05) by ϳ50% but not to KCl. However, in endothelium-denuded or N G -nitro-L-arginine methyl ester (L-NAME) (100 M)-treated rings, wortmannin reduced responses to phenylephrine and KCl (P Ͻ 0.05). Furthermore, the rhokinase inhibitor Y-27632 (R-[ϩ]-trans-N-[4-pyridyl]-4-[1-aminoethyl]-cycloheaxanecarboxamide; 1 M) abolished responses to phenylephrine, and this effect was partially reversed by wortmannin or L-NAME. The ability of wortmannin to oppose the effect of rho-kinase inhibition on contractions to phenylephrine was L-NAME-sensitive. In aortas from angiotensin II-induced hypertensive rats, relaxation to acetylcholine (10 M) was impaired (P Ͻ 0.05), and vasoconstriction by phenylephrine was markedly enhanced and not further augmented by wortmannin. These data suggest that endothelial PI3K-induced NO production can modulate GPCR agonist-induced vascular contraction and that this effect is impaired in hypertension in association with endothelial dysfunction. In addition, endothelial rho-kinase may act to suppress PI3K activity and, hence, attenuate NO-mediated relaxation and augment GPCR-dependent contraction.

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Section: Discussionmentioning

confidence: 99%

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Budzyn

Marley²,

Sobey³

2005

J Pharmacol Exp Ther

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“…Studies in neurons and vascular smooth muscle cells indicate that the LTCC is regulated by the PI 3-kinase signaling pathway in these cell types (6,7). Studies by our laboratory and other investigators indicate that PI 3-kinase signaling also modulates LTCC function in cardiac myocytes (8 -10).…”

mentioning

confidence: 83%

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Jiang

et al. 2007

Diabetes

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OBJECTIVE-Contraction of cardiac myocytes is initiated byCa 2ϩ entry through the voltage-dependent L-type Ca 2ϩ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling. RESEARCH DESIGN AND METHODS-We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2 Akita mutation versus nondiabetic littermates.RESULTS-Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased L-type Ca 2ϩ current (I Ca,L ) density in myocytes compared with control nondiabetic littermates. The lower I Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P 3 stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P 3 infusion eliminated only the difference in voltage dependence of steady-state inactivation of I Ca,L .CONCLUSIONS-Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca 2ϩ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility. Diabetes 56:2780-2789, 2007 C ardiac complications are an important cause of morbidity and mortality in type 1 diabetic patients. This is partly due to the presence of hypertension and coronary artery disease, which are commonly associated with diabetes. Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2-5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force. However, the molecular mechanism that underlies the LTCC defect in diabetic myocytes is unclear.Class I phosphatidylinositol (PI) 3-kinases preferentially phosphorylate PI 4,5-bisphosphate [PI(4,5)P 2 ] to form phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] in vivo and exhibit substantial activation in response to stimulation with insulin or other hormones. Studies in neuron...

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“…It is generally believed that free G␤␥ subunits exert their influence via Src family kinase (SFK) and phosphatidylinositol 3-kinase (PI3 kinase) (Viard et al, 1999;Macrez et al, 2001;Quignard et al, 2001). In the hypothalamus, SFK (Charpantier et al, 2005) and PI3 kinase (CardonaGomez et al, 2002;Sahu, 2003;Lin et al, 2004) are functionally active.…”

Section: Signaling Pathway Of G␤␥ Subunitsmentioning

confidence: 99%

Dominant Role of βγ Subunits of G-Proteins in Oxytocin-Evoked Burst Firing

Wang

Hatton²

2007

J. Neurosci.

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Pulsatile neuropeptide secretion is associated with burst firing patterns; however, intracellular signaling cascades leading to bursts remain unclear. We explored mechanisms underlying burst firing in oxytocin (OT) neurons in the supraoptic nucleus in brain slices from lactating rats. Application of 10 pM OT for 30 min or progressively rising OT concentrations from 1 to 100 pM induced burst firing in OT neurons in patch-clamp recordings. Burst generation was blocked by OT antagonist and ionotropic glutamate receptor blockers or tetanus toxin. Blocking G-protein activation with suramin or intracellular GDP-␤-S, but not intracellularly administered antibody against the OT-receptor (OTR) C terminus, blocked bursts. Moreover, pretreatment of slices with pertussis toxin, an inhibitor of G i/oproteins, did not block OT-evoked bursts, suggesting that G i /G o activation is unnecessary for burst generation. Thus, we further examined G␣ q/11 -associated signaling pathways in OT-evoked bursts. Inhibition of phospholipase C or RhoA/Rho kinase did not block bursts. Activation of G␤␥ subunits using myristoylated G␤␥-binding peptide (mSIRK) caused bursts, whereas intracellularly loaded antibody against G␤ subunit blocked OT-evoked bursts. Blocking Src family kinase, but not phosphatidylinositol 3-kinase, occluded OT-evoked bursts. Similar to the effects of OT on EPSCs, mSIRK inhibited tonic EPSCs and elicited EPSC clustering. Finally, suckling caused dissociation of OTRs and G␤ subunits from G␣ q/11 subunits shown by coimmunoprecipitation and immunocytochemistry, supporting crucial roles for OTRs and G␤␥ subunits in the milk-ejection reflex. We conclude that G␤␥ subunits play a dominant role in burst firing evoked by applied OT or by suckling.

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Phosphoinositide 3-Kinase Isoforms Selectively Couple Receptors to Vascular L-Type Ca ²⁺ Channels

Cited by 88 publications

References 35 publications

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Dominant Role of βγ Subunits of G-Proteins in Oxytocin-Evoked Burst Firing

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Phosphoinositide 3-Kinase Isoforms Selectively Couple Receptors to Vascular L-Type Ca 2+ Channels

Cited by 88 publications

References 35 publications

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Dominant Role of βγ Subunits of G-Proteins in Oxytocin-Evoked Burst Firing

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Phosphoinositide 3-Kinase Isoforms Selectively Couple Receptors to Vascular L-Type Ca ²⁺ Channels