Chronic receptor-mediated activation of G<sub>i/o</sub>proteins alters basal t-tubular and sarcolemmal L-type Ca<sup>2+</sup>channel activity through phosphatases in heart failure

Kashihara, Toshihide; Nakada, Tsutomu; Shimojo, Hisashi; Horiuchi-Hirose, Miwa; Gomi, Simmon; Shibazaki, Toshihide; Sheng, Xiaona; Hirose, Masao; Hongo, Minoru; Yamada, Mitsuhiko

doi:10.1152/ajpheart.00589.2011

Cited by 13 publications

(12 citation statements)

References 40 publications

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“…In cardiac ventricular myocytes, for example, PTx by itself does not change L‐type calcium current under physiological conditions, but PTx prevents isoprenolol‐induced calcium augmentation, thus contributing to a negative inotropic effect (Kashihara et al . ). However, it remains unknown whether neuronal calcium channels are subject to PTx modulation in a similar way.…”

Section: Discussionmentioning

confidence: 97%

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Tang

Han

et al. 2015

Journal of Neurochemistry

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Increased calcium influx secondary to glutamate induced excitotoxicity initiates and potentiates devastating pathological changes following ischemic stroke. Pertussis toxin (PTx), a Gprotein blocker, is known to suppress intracellular calcium accumulation. We hypothesize that PTx can protect against stroke by blocking calcium influx. In a permanent middle cerebral artery occlusion model, PTx (1000 ng) was given intraperitoneally 30 min after inducing stroke. Magnetic Resonance Imaging of perfusion and T2-weighted brain scans were obtained to evaluate cerebral blood flow (CBF) and infarct volume. Primary neuronal culture was used to test glutamate induced excitotoxicity and calcium influx. We established a non-linear exponential curve model to minimize variations in animal cerebrovasculature. A reduction of 40-60% in relative CBF was a critical window where infarct volume started to increase as rCBF reduced. PTx showed maximal effects in reducing infarct volume at this window. In vitro studies further demonstrated PTx increased neuronal cell survival by decreasing glutamate-induced calcium influx into neurons and preventing neurons from apoptosis. PTx salvages the ischemic penumbra by blocking calcium influx. This provides us a new mechanism upon which experimental therapies can be explored to treat ischemic stroke.

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Section: Discussionmentioning

confidence: 97%

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Tang

Han

et al. 2015

Journal of Neurochemistry

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“…To study whether renin inhibition after activation of the CaSR is coupled to the Gi protein, we incorporated 100 ng/ml of pertussis toxin (PTX, EMD Chemicals, Philadelphia, PA) as has been previously shown to inhibit Gi in isolated JG cells (37) and other cells in vitro (1,34,35,37,47,52) into our protocols, and activated the CaSR using cinacalcet as above. In protocols incubating JG cells, we first pretreated cell for 3 h with either 100 ng/ml PTX or its vehicle (DMSO, 1/1,000 dilution) to block G i.…”

Section: G I In the Casr-mediated Inhibition Of Renin Releasementioning

confidence: 99%

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP₃pathway and the ryanodine receptor

Ortiz-Capisano

Reddy

Méndez

et al. 2013

American Journal of Physiology-Renal Physiology

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The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through Gq and/or Gi. Activation of Gq stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP3), releasing calcium from intracellular stores. Gi stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP3 and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells (n ϭ 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 Ϯ 7% of control (P Ͻ 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 Ϯ 11% of control). The IP3 inhibitor 2-APB also reversed inhibition of renin from 56 Ϯ 6 to 104 Ϯ 11% of control (P Ͻ 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 Ϯ 8 to 118 Ϯ 22% of control (P Ͻ 0.01). Combining inhibition of IP3 and RyR was not additive. Gi inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 Ϯ 12 to 41 Ϯ 8% of control, P Ͻ 0.001). We conclude stimulating JG cell CaSR activates G q, initiating the PLC/IP3 pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition. calcium; renin; calcium-sensing receptor; inositol-3 phosphate; phospholipase C; protein kinase A; ryanodine receptor THE CALCIUM-SENSING RECEPTOR (CaSR) is a G protein-coupled 7-transmembrane receptor (33) found in the parathyroid gland, blood vessels, and kidney (18). In the parathyroid gland where CaSR was first described, high extracellular calcium results in decreased parathyroid hormone secretion (21). This is mediated by calcium activation of the CaSR, stimulating the G proteins G q and/or G i . In the parathyroid, activation of G q stimulates phospholipase C (PLC), producing diacylglycerol and inositol 1,4,5-trisphosphate (IP 3 ), the latter of which releases calcium from intracellular stores bound in the endoplasmic reticulum (ER) (48). G i stimulation leads to the inhibition of cAMP formation (16,48). Either pathway results in suppressing parathyroid hormone release.In the secretory juxtaglomerular (JG) cells, like the parathyroids, increased calcium results in the suppression of renin secretion (21,43,44). We have previously reported, both in vitro (44) and in vivo (6), that the JG cells contain CaSR, and that increased media calcium or activation of the CaSR with a calcimimetic (6, 43, 44) leads to suppression of renin secretion. JG cells synthesize, store, and release renin, the rate-limiting enzyme involved in the formation of angiotensin II (9). The cyclic nucleotide cAMP ...

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“…This phosphatase has been postulated to regulate the availability of LTCCs in ventricular myocytes by PKA-mediated phosphorylation at a site distinct from Ser1928 (38). Moreover, recent data in a mouse model of Iso-induced heart failure suggest that PP1 and PP2A may differentially affect subcellular populations of LTCCs in ventricular myocytes (21). Second, we did not directly assess the phosphorylation status of Ca v 1.2 channels in post-MI and sham-operated hearts.…”

Section: Discussionmentioning

confidence: 96%

Pyruvate restores β-adrenergic sensitivity of L-type Ca²⁺channels in failing rat heart: role of protein phosphatase

Zheng

Li²,

Tang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca(2+) channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca(2+) channels in a rat infarction model of heart failure. Patch-clamp recordings of L-type Ca(2+) current (I(Ca,L)) from ventricular myocytes isolated from infarcted hearts showed a blunted response to intracellular cAMP that was reversed by treatment with exogenous pyruvate. Biochemical studies showed that basal and cAMP-stimulated protein kinase A activities were similar in infarcted and sham-operated hearts, whereas molecular analysis also found that binding of protein kinase A to the α(1C) subunit of voltage-gated Ca(2+) channel isoform 1.2 was not different between groups. By contrast, protein phosphatase 2A (PP2A) activity and binding to α(1C) were significantly less in infarcted hearts. The PP2A inhibitor okadaic acid markedly increased I(Ca,L) in sham-operated myocytes, but this response was significantly less in myocytes from infarcted hearts. However, pyruvate normalized I(Ca,L) stimulation by okadaic acid, and this effect was blocked by inhibitors of thioredoxin reductase, implicating a functional role for the redox-active thioredoxin system. Our data suggest that blunted β-adrenergic stimulation of I(CaL) in failing hearts results from hyperphosphorylation of Ca(2+) channels secondary to oxidation-induced impairment of PP2A function. We propose that the redox state of Ca(2+) channels or PP2A is controlled by the thioredoxin system which plays a key role in Ca(2+) channel remodeling of the failing heart.

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Chronic receptor-mediated activation of G_i/oproteins alters basal t-tubular and sarcolemmal L-type Ca²⁺channel activity through phosphatases in heart failure

Cited by 13 publications

References 40 publications

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP₃pathway and the ryanodine receptor

Pyruvate restores β-adrenergic sensitivity of L-type Ca²⁺channels in failing rat heart: role of protein phosphatase

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Chronic receptor-mediated activation of Gi/oproteins alters basal t-tubular and sarcolemmal L-type Ca2+channel activity through phosphatases in heart failure

Cited by 13 publications

References 40 publications

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP3pathway and the ryanodine receptor

Pyruvate restores β-adrenergic sensitivity of L-type Ca2+channels in failing rat heart: role of protein phosphatase

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Chronic receptor-mediated activation of G_i/oproteins alters basal t-tubular and sarcolemmal L-type Ca²⁺channel activity through phosphatases in heart failure

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP₃pathway and the ryanodine receptor

Pyruvate restores β-adrenergic sensitivity of L-type Ca²⁺channels in failing rat heart: role of protein phosphatase