Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity

Abstract

Background:Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca2+ channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsies. Earlier studies predominantly targeted on Cav2.1 P/Q-type and Cav3.2 T-type Ca2+ channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Cav2.3 R-type Ca2+ channel which exhibits an intriguing role in ictogenesis and seizure propagation. Cav2.3 R-type voltage gated Ca2+ channels (VGCC) emerged to be important factors in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and cellular epileptiform activity, e.g. in CA1 neurons. They also serve as potential target for various antiepileptic drugs, such as lamotrigine and topiramate.Objective: This review provides a summary of structure, function and pharmacology of VGCCs and their fundamental role in cellular Ca2+ homeostasis. We elaborate the unique modulatory properties of Cav2.3 R-type Ca2+ channels and point to recent findings in the proictogenic and proneuroapoptotic role of Cav2.3 R-type VGCCs in generalized convulsive tonic–clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity.Conclusion:Development of novel Cav2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

“…However, the electrotaxis of T98G is not dependent on calmodulin by inhibition with calmidazolium (P > .99, FIG. 3) and Ni 2+ treatment has no inhibition on T98G cells (P > .99) which has partial inhibition on R-type VGCC 103,106 . These results imply an alternative mechanism might be at play.…”

Voltage-Gated Calcium Channels and Molecular Features

“…Aynı zamanda, iskelet kası, nöroendokrin hücreler ve talamik nöronlar gibi heyecan verici diğer dokularda ve ayrıca uyarılmayan fibroblastlar, osteoblastlar ve astrositler gibi hücrelerde de tanımlanmıştır. Birçok dokuda bulunmasına rağmen sinoatrial düğüm, atrioventriküler düğüm, nöronal hücre, kalp, plasenta ve düz kaslarda daha çok yoğunlaştığı gösterilmiştir 55 59 . İki alt aileden gelen CaV1 ve CaV2 olarak bilinen HVA Ca 2+ kanalları ve bunları kodlayan genler düşük dizi homolojisinden beklendiği üzere nispeten erken dönemlerde ortaya çıkmışlardır.…”

“…Ayrıca, Cav2.3 Ca 2+ kanalları, iskemik nöronal hasarda koruyucu bir işlev sergilediği ve insanlarda subaraknoid kanamayı takiben vazospazmlara katkıda bulunduğu yapılan çalışmalarla gösterilmiştir. Özellikle hücrenin içine giren Ca 2+ ve Zn 2+ 'nin, hücreler arası sinyal iletim kaskadlarında karmaşık etkileri olduğu unutulmamalıdır59 .…”

Unconjugated bilirubin modulates neuronal signaling only in wild‐type mice, but not after ablation of the R‐type/Cav2.3 voltage‐gated calcium channel

“…In the central nervous system, voltage‐gated calcium channels (VGCCs) regulate a variety of processes, including hormonal communication, modulation of cell migration, triggering of muscle contraction, and many other processes . They contribute to synaptic transmission and calcium homeostasis in different neuronal networks including the additional processes like disruption of neuronal networks . Moreover, there is convincing evidence that subarachnoid hemorrhage (SAH) can alter the expression profile of calcium channels in cerebral arteries.…”