Genistein Inhibits Cardiac L-Type Ca<sup>2+</sup>Channel Activity by a Tyrosine Kinase-Independent Mechanism

Belevych, Andriy E.; Warrier, Sunita; Harvey, Robert D.

doi:10.1124/mol.62.3.554

Cited by 45 publications

(34 citation statements)

References 29 publications

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“…4B). Although genistein is a potent PTK inhibitor and is the most frequently used PTK inhibitor, its specificity has raised concerns, because both PTK-dependent and -independent effects have been found (32,33). We verified the PTK dependency of I SP-O on GM DRG neurons by using an inactive structural analog of genistein, daidzein, which had no effect on I SP-O (Fig.…”

Section: Resultsmentioning

confidence: 83%

An antinociceptive role for substance P in acid-induced chronic muscle pain

Weinan

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Release of substance P (SP) from nociceptive nerve fibers and activation of its receptor neurokinin 1 (NK1) are important effectors in the transmission of pain signals. Nonetheless, the role of SP in muscle pain remains unknown. Here we show that a single i.m. acid injection in mice lacking SP signaling by deletion of the tachykinin precursor 1 (Tac1) gene or coadministration of NK1 receptor antagonists produces long-lasting hyperalgesia rather than the transient hyperalgesia seen in control animals. The inhibitory effect of SP was found exclusively in neurons expressing acid-sensing ion channel 3, where SP enhances M-channel-like potassium currents through the NK1 receptor in a G protein-independent but tyrosine kinase-dependent manner. Furthermore, the SP signaling could alter action potential thresholds and modulate the expression of TTX-resistant sodium currents in medium-sized muscle nociceptors. Thus, i.m. SP mediates an unconventional NK1 receptor signal pathway to inhibit acid activation in muscle nociceptors, resulting in an unexpected antinociceptive effect against chronic mechanical hyperalgesia, here induced by repeated i.m. acid injection.is an undecapeptide belonging to the tachykinin small-peptide family (1). SP is generated in primary nociceptive sensory neurons (nociceptors) and is released with noxious stimulation (2). The release from cutaneous peripheral terminals induces neurogenic inflammation and release from central terminals enhances the glutamate-dependent excitatory postsynaptic potential, thus leading to central sensitization (3-5). Although sensory neurons in muscle also contain SP, i.m. SP injection evokes a very low level of neurogenic inflammation and no pain (6, 7).Accumulating evidence has suggested that muscle pain might be closely related to acidosis and activation of proton-sensing ion channels (8-10). Lactate and ATP sensitize this acid activation (11,12). Human and animal studies have revealed that acidosis is an effective trigger of muscle pain. Thus, chronic muscle pain can be induced in rodents by repeated i.m. injection of acid (13,14), by i.m. injection of complete Freund's adjuvant (CFA), carrageenan, capsaicin, or proinflammatory cytokines (15-18), by arterial occlusion (19), and by eccentric muscle contraction (20). These stimuli might correspond to muscle pain related to acidosis, inflammatory and ischemic myalgia, or delayed-onset muscle soreness. Although these models might not reflect fully the complicated human pain conditions, and although repetitive acidosis is not known to produce chronic pain or central sensitization in humans, these rodent models are useful for probing the underlying mechanisms and analgesic modulation of chronic muscle pain. For instance, acid-sensing ion channel 3 (ASIC3) is essential for triggering acid-induced mechanical hyperalgesia in models of i.m. injection of acid, CFA, or carrageenan (13,17,(21)(22)(23). Coinjection of neurotrophin-3 reverses the acid-induced chronic hyperalgesia (24). Also, some muscle-derived pain can be attenu...

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Section: Resultsmentioning

confidence: 83%

An antinociceptive role for substance P in acid-induced chronic muscle pain

Weinan

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The voltage dependence of Ca 2ϩ channel activation and inactivation was determined as described previously. 32 Parameters for the voltage dependence of activation were obtained from the least squares fit of data points to the equation:…”

Section: Data Acquisition and Analysismentioning

confidence: 99%

Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2

Sims

Reisenweber

Viswanathan

et al. 2008

Circulation Research

103

121

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Abstract-In congenital and acquired long QT type 2, women are more vulnerable than men to Torsade de Pointes. In prepubertal rabbits (and children), the arrhythmia phenotype is reversed; however, females still have longer action potential durations than males. Thus, sex differences in K ϩ channels and action potential durations alone cannot account for sex-dependent arrhythmia phenotypes. The L-type calcium current (I Ca,L ) is another determinant of action potential duration, Ca 2ϩ overload, early afterdepolarizations (EADs), and Torsade de Pointes. Therefore, sex, age, and regional differences in I Ca,L density and in EAD susceptibility were analyzed in epicardial left ventricular myocytes isolated from the apex and base of prepubertal and adult rabbit hearts. In prepubertal rabbits, peak I Ca,L at the base was 22% higher in males than females (6.4Ϯ0.5 versus 5.0Ϯ0.2 pA/pF; PϽ0.03) and higher than at the apex (6.4Ϯ0.5 versus 5.0Ϯ0.3 pA/pF; PϽ0.02). Sex differences were reversed in adults: I Ca,L at the base was 32% higher in females than males (9.5Ϯ0.7 versus 6.4Ϯ0.6 pA/pF; PϽ0.002) and 28% higher than the apex (9.5Ϯ0.7 versus 6.9Ϯ0.5 pA/pF; PϽ0.01). Apex-base differences in I Ca,L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca v 1.2␣ levels varied with sex, maturity, and apex-base, with differences similar to variations in I Ca,L ; optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo-Rudy simulations concur that I Ca,L elevation promotes EADs and is an important determinant of long QT type 2 arrhythmia phenotype, most likely by reducing repolarization reserve and by enhancing Ca 2ϩ overload and the propensity for I Ca,L reactivation. (Circ Res. 2008;102:e86 -e100.)

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“…The current elicited during the test pulse was normalized to the magnitude of the current recorded during a pretest pulse to 0 mV, which preceded each conditioning pulse. This corrected for changes in current magnitude due to rundown (Belevych et al, 2002). **Significantly different when compared to the absence of PAO (Po0.01).…”

Section: Dtt Blocks Pao-induced Stimulatory Effectsmentioning

confidence: 99%

“…The voltage dependence of channel activation and inactivation was determined as described previously (Belevych et al, 2002). For these experiments, voltage-clamp protocols were repeated in the presence and absence of 100 mM CdCl 2 , and the L-type Ca 2 þ current was defined as the Cd 2 þ -sensitive difference current.…”

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confidence: 99%

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide

Sims

Harvey

2004

British J Pharmacology

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1 Phenylarsine oxide (PAO) is commonly used to inhibit tyrosine phosphatase activity. However, PAO can affect a variety of different processes because of its ability to promote sulfhydryl oxidation. In the present study, we investigated the effects that PAO has on basal and b-adrenergically stimulated L-type Ca 2 þ channel activity in isolated cardiac myocytes. 2 Extracellular application of PAO transiently stimulated the basal L-type Ca 2 þ channel activity, whereas it irreversibly inhibited protein kinase A (PKA)-dependent regulation of channel activity by isoproterenol, forskolin and 8-CPT-cAMP (8-p-chlorophenylthioadenosine 3 0 ,5 0 -cyclic monophosphate). PAO also inhibited channel activity irreversibly stimulated in the presence of adenosine 5 0 -(3-thiotriphosphate) tetralithium salt. 3 Neither the stimulatory nor the inhibitory effects of PAO were affected by the tyrosine kinase inhibitor lavendustin A, suggesting that tyrosine phosphorylation is not involved. 4 Extracellular application of the sulfhydryl-reducing agent dithiothreitol (DTT) antagonized both the stimulatory and inhibitory effects of PAO. Yet, following intracellular dialysis with DTT, only the inhibitory effect of PAO was antagonized. 5 The inhibitory effect of PAO was mimicked by intracellular, but not extracellular application of the membrane impermeant thiol oxidant 5,5 0 -dithio-bis(2-nitrobenzoic acid).6 These results suggest that the stimulatory effect of PAO results from oxidation of sulfhydryl residues at an extracelluar site and the inhibitory effect is due to redox regulation of an intracellular site that affects the response of the channel to PKA-dependent phosphorylation. It is concluded that the redox state of the cell may play a critical role in modulating b-adrenergic responsiveness of the Ltype Ca 2 þ channel in cardiac myocytes.

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Genistein Inhibits Cardiac L-Type Ca²⁺Channel Activity by a Tyrosine Kinase-Independent Mechanism

Cited by 45 publications

References 29 publications

An antinociceptive role for substance P in acid-induced chronic muscle pain

An antinociceptive role for substance P in acid-induced chronic muscle pain

Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide

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Genistein Inhibits Cardiac L-Type Ca2+Channel Activity by a Tyrosine Kinase-Independent Mechanism

Cited by 45 publications

References 29 publications

An antinociceptive role for substance P in acid-induced chronic muscle pain

An antinociceptive role for substance P in acid-induced chronic muscle pain

Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca2+ channel activity by phenylarsine oxide

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Genistein Inhibits Cardiac L-Type Ca²⁺Channel Activity by a Tyrosine Kinase-Independent Mechanism

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide