PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane

Viard, Patricia; Butcher, Adrian J.; Halet, Guillaume; Davies, Anthony; Nürnberg, Bernd; Heblich, Fay; Dolphin, Annette C.

doi:10.1038/nn1300

Cited by 227 publications

(204 citation statements)

References 38 publications

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“…7) is consistent with the hypothesis that impaired LTCC trafficking contributes to the reduction in I Ca,L density in diabetic myocytes. Our results are also consistent with a model proposed by Viard et al (13) in which PI(3,4,5)P 3 activation of Akt results in phosphorylation of the LTCC ␤2a-subunit, which leads to increased trafficking of the channels to the cell surface. It was reported that the neuronal N-type Ca 2ϩ channel rapidly internalized and reappeared on the cell surface after GABA receptor stimulation within 80 s (34).…”

Section: Discussionsupporting

confidence: 93%

“…PI(3,4,5)P 3 and insulin stimulation of I Ca,L is blocked by taxol treatment. It was reported that activation of PI 3-kinase stimulates I Ca,L density through Akt-mediated phosphorylation of ␤2a-subunits, leading to increased trafficking of exogenously expressed LTCC to the plasma membrane in COS7 cells (13). We hypothesized that PI(3,4,5)P 3 infusion stimulates trafficking of the LTCC to the cell surface of diabetic cardiac myocytes, thus increas- ing I Ca,L density.…”

Section: Resultsmentioning

confidence: 95%

“…Cardiac LTCCs are mostly composed of ␣1C-and ␤2a-isoforms, although other ␤-variants are also present (12). In a heterologous expression system, PI 3-kinase signaling stimulated I Ca,L density through Aktmediated phosphorylation of ␤2a-subunits, leading to increased trafficking of the LTCC to the plasma membrane (13). The protein kinase Akt (also known as PKB) is an important downstream effector of PI 3-kinase that is activated upon binding to PI(3,4,5)P 3 .…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

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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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“…It is the dominantly expressed Ca v 1.2 b-subunit in the heart. The phosphatidylinositol-3-kinase pathway is-via interaction with Ca v b2-involved in ensuring a sufficient expression of Ca v 1.2 on the plasma membrane [Viard et al, 2004].…”

Section: Brs4-mutations In Cacnb2mentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

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“…Phosphorylation sites on the ␣ 1 subunit were invoked for PKA (6 -8), CaMKII (9 -11), PKG (12,13), Akt/PKB (14,15), and by PKC (16 -19). In addition, phosphorylation sites in the Ca v ␤ 2 subunit were reported for PKA (20) at Ser 479/480 (rabbit protein sequence (rbs)) (21), CaMKII (22) at Thr 500 (rbs), PKG (12) at Ser 496 (rbs), and Akt/PKB (14,15,23,24) at Ser 576 (rbs). The amino acids modified by protein kinases in Ca v ␤ 2 or Ca v 1.2 in the protein sequence from rabbit, rat, and mouse are listed in supplemental Table 1.…”

mentioning

confidence: 99%

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

Brandmayr

Poomvanicha

Domes

et al. 2012

Journal of Biological Chemistry

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Background: ␤-Adrenergic receptors stimulate cardiac I Ca via PKA-dependent phosphorylation. Results: Deletion of the C-terminal phosphorylation sites in the ␤ 2 gene did not affect isoproterenol-stimulated I Ca . Conclusion: Phosphorylation of the C terminus of the ␤ 2 subunit in vivo does not contribute to ␤-adrenergic regulation of I Ca . Significance: The PKA-dependent regulation of I Ca does not require the C terminus of the ␤ 2 subunit.

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PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane

Cited by 227 publications

References 38 publications

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

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

The genetic basis of Brugada syndrome: A mutation update

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

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