Pharmacology
editT-type calcium channels are involved in diseases such as absence epilepsy[1] , diabetes[2] , and several forms of cancer[3].
Absence Epilepsy
editExperiments on the Genetic Absence Epilepsy Rat of Strasbourg (GAERS) suggested that absence epilepsy in the rat was linked to T-type channel protein expression[1] . In fact, neurons isolated from the reticular nucleus of the thalamus of the GAERS showed 55% greater T-type currents, and these currents were attributed to an increase in the Cav3.2 mRNA, according to Tally et al[1] . suggesting that T-type protein expression was up regulated in the GAERS. Further experiments on the GAERS showed that, indeed, the expression of T-type calcium channels play a key role in seizures caused by absence epilepsy in the GAERS[1] . Also, other evidence suggest that T-type calcium channel expression is not only up regulated in absence epilepsy, but also in other forms of epilepsy as well[1].
Cancer
editT-type Calcium channels are expressed in different human cancers such as breast, colon, prostate, insulinoma, retinoblastoma, leukemia, ovarian, and melanoma, and they also play key roles in proliferation, survival, and the regulation of cell cycle progression in these forms of cancer . This was demonstrated through studies that showed that down regulating T-type channel isoforms, or just blocking the T-type calcium channels caused cytostatic effects in cancer cells such as [gliomas]], breast, melanomas, and ovarian, esophageal, and colorectal cancers . Some of the most notorious forms of cancer tumors contain cancer stem cells (CSC), which makes them particularly resistant to any cancer therapy . Furthermore, there is evidence that suggests that the presence of the CSC in human tumors may be associated with the expression of T-type calcium channels in the tumors[2] .
Diabetes
editThe Cav3.2 isoform of T-type calcium channels has been found to cause neuropathic pain in animal models with peripheral diabetic neuropathy (PDN) . Actually, the Cav3.2 isoform of T-type calcium channels enhances excitability of nociceptors in animals with type 1 or 2 PDN . As a result, this enhanced excitability causes neuropathic pain[3] .
Current research
editStudies have shown that calcium channel blockers (CCB) such as mibefradil can also block L-type calcium channels, other enzymes, as well as other channels[3] . Consequently, research is still being conducted to design highly selective drugs that can target T-type calcium channels alone[3] . Furthermore, since T-type calcium channels are involved in proliferation, survival and cell cycle progression of these cells, they are potential targets for anticancer therapy[3] . Like mentioned above, blockage or down regulation of the T-type calcium channels causes cytostasis in tumors; but this blockage or down regulation of the T-channels may also induce cytotoxic effects. Consequently, it is not yet clear what the benefits or disadvantages of targeting T-type calcium channels in anticancer therapy are[3] . On the other hand, a combined therapy involving administration of a T-type channel antagonist followed by cytotoxic therapy is currently in its clinical trial phase[3] . In addition, drugs that target the CaV3.2 isoform (responsible for development of neuropathic pain in PDN) are associated with serious side effects[2] . As a result, research to improve or design new drugs is currently on-going[2] .
Notes
edit- ^ a b c d e Nelson, M.; Todorovic, S.; Perez-Reyes, E. (1 June 2006). "The Role of T-Type Calcium Channels in Epilepsy and Pain". Current Pharmaceutical Design. 12 (18): 2189–2197. doi:10.2174/138161206777585184. PMID 16787249.
- ^ a b c d Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna (31 January 2014). "Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy". Pflügers Archiv - European Journal of Physiology. 466 (4): 701–706. doi:10.1007/s00424-014-1452-z. PMID 24482063.
- ^ a b c d e f g Dziegielewska, Barbara; Gray, Lloyd S.; Dziegielewski, Jaroslaw (22 January 2014). "T-type calcium channels blockers as new tools in cancer therapies". Pflügers Archiv - European Journal of Physiology. 466 (4): 801–810. doi:10.1007/s00424-014-1444-z. PMID 24449277.