Pharmacology of Cav3 (T-Type) Channels

Ertel, Eric A.

doi:10.1007/978-1-4419-9254-3_6

Cited by 7 publications

(11 citation statements)

References 424 publications

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“…Cav3 channels (Cav3.1, Cav3.2, and Cav3.3 low‐voltage‐activated T‐type channels) are expressed in nervous tissue, in sinoatrial node in many species, and even in nonexcitable cells 121,122. Somewhat surprisingly, given this wide expression, Cav3 channels appear to be comparatively safe targets for an inhibitor.…”

Section: Cav3 Channels: Sleep Pain Seizure and Obesitymentioning

confidence: 99%

“…Although studies of knockout mice imply that the antihypertensive effect of mibefradil is mediated through Cav1.2 and not Cav3 channels,131 mibefradil is equally or more potent on Cav3 in vitro —suggesting that if it inhibits Cav1.2 in vivo , it likely inhibits Cav3 in vivo , and that the safety profile of Posicor ® reflects any adverse events that would result from Cav3 inhibition. Similarly, the safety profiles of drugs including Orap ® (pimozide, antipsychotic132,133), Dilantin ® (phenytoin, antiepileptic134,135), and DHPs including Nimotop ® (nimodipine136) (for review see Ref 121) can be interpreted to suggest no prohibitive liability to inhibition of Cav3 channels, including those in the CNS. These drugs are given clinically and inhibit T‐type channels with potency more or less comparable to their presumed targets, suggesting that T‐type inhibition is safe.…”

Section: Cav3 Channels: Sleep Pain Seizure and Obesitymentioning

confidence: 99%

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Calcium ion channels: challenges and successes in drug discovery

McDonough

2012

WIREs Membr Transp Signal

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There are both opportunities and challenges in developing improved or novel therapeutics based on targeting voltage-gated calcium channels. Calcium channels are technically difficult with respect to target-based drug discovery but unquestionably are key points for influencing human physiology and pathophysiology. Many marketed drugs, including nifedipine, nimodipine, ethosuximide, pregabalin, and ziconotide, exert therapeutic efficacy via inhibition of calcium channels. Although there is no obvious path to improving these existing drugs, recent clinical results with dihydropyridine drugs point to testable strategies for treatment of Parkinson's disease and possibly other CNS disorders by inhibiting L-type calcium channels. Roles of T-type calcium channels in pain and in abnormal sleep are plausible and may soon be tested with clinical trials of novel therapeutics. Success with any of these trials certainly will be followed by intensive efforts for further refinements around the target class.

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Section: Cav3 Channels: Sleep Pain Seizure and Obesitymentioning

confidence: 99%

Section: Cav3 Channels: Sleep Pain Seizure and Obesitymentioning

confidence: 99%

Calcium ion channels: challenges and successes in drug discovery

McDonough

2012

WIREs Membr Transp Signal

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“…They are useful research tools and were used in the classification of these channels. T-type currents are insensitive to these toxins [12,4,24] and to TTX [29]. Kurtoxin, a 63 amino acid protein from the Parabuthus transvaalicus scorpion, was reported to bind to the a1G channel with high affinity and to inhibit it and the a1H channel with high potencies, 15-60 nM [35].…”

Section: Toxinsmentioning

confidence: 99%

“…Channel expression levels are often present at higher densities in embryonic and neonatal systems, where there is significant growth, and reduced in mature cells, including neuronal and cardiac atrial and ventricular myocytes [24]. In models of cardiac hypertrophy and cardiomyopathy mibefradil reduced remodeling [84], suggesting a role for T-type channels in these growth processes.…”

Section: Indicationsmentioning

confidence: 99%

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Drugs Active at T‐type Ca ²⁺ Channels

Connolly¹,

Barrow²

2006

Methods and Principles in Medicinal Chemistry

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Regulation of L‐type Ca⁺⁺ currents and process morphology in white matter oligodendrocyte precursor cells by golli‐myelin proteins

Fulton

Paez

Fisher

et al. 2010

Glia

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The golli myelin basic proteins are expressed in oligodendroglial precursor cells (OPCs) where they play a role in regulating Ca(2+) homeostasis. During depolarization, they influence process outgrowth and migration through their action on voltage-operated Ca(2+) channels (VOCCs). To identify ion channels that are modulated by golli, we examined the electrophysiological properties of VOCCs in OPCs in the white matter of golli knock-out and control mice. OPCs exhibited two distinct Ca(2+) channels, which were distinguished by their voltage dependence and pharmacological profiles and which exhibited many of the hallmarks of LVA/T-type and HVA/L-type Ca(2+) channels. The density of high-voltage-activated (HVA) currents was reduced in OPCs recorded in golli-KO tissue, while low-voltage-activated (LVA) currents remained unaltered in these cells. These data indicate that golli exerts an exclusive influence on L-type Ca(2+) channels in OPCs. Oligodendrocytes (OLs) also displayed LVA and HVA currents, although the density of these currents was much reduced at this developmental stage. These currents were not altered in golli-KO OLs showing the influence of golli on L-type Ca(2+) channels is restricted to a specific time-window during the course of oligodendroglial development. The actions of golli on OPC L-type Ca(2+) channels were accompanied by changes in process morphology, including a reduction in process complexity and the appearance of enlarged varicosities that decorated these cellular processes. These data on L-type Ca(2+) channels and process development provide in situ evidence for the influence of golli on VOCCs, and offer an explanation for the hypomyelination observed in the brains of golli-KO mice.

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Pharmacology of Cav3 (T-Type) Channels

Cited by 7 publications

References 424 publications

Calcium ion channels: challenges and successes in drug discovery

Calcium ion channels: challenges and successes in drug discovery

Drugs Active at T‐type Ca ²⁺ Channels

Regulation of L‐type Ca⁺⁺ currents and process morphology in white matter oligodendrocyte precursor cells by golli‐myelin proteins

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Pharmacology of Cav3 (T-Type) Channels

Cited by 7 publications

References 424 publications

Calcium ion channels: challenges and successes in drug discovery

Calcium ion channels: challenges and successes in drug discovery

Drugs Active at T‐type Ca 2+ Channels

Regulation of L‐type Ca++ currents and process morphology in white matter oligodendrocyte precursor cells by golli‐myelin proteins

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Product

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About

Drugs Active at T‐type Ca ²⁺ Channels

Regulation of L‐type Ca⁺⁺ currents and process morphology in white matter oligodendrocyte precursor cells by golli‐myelin proteins