Review: Ca_v2.3 R-type Voltage-Gated Ca²⁺ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity

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 Ca_v2.1 P/Q-type and Ca_v3.2 T-type Ca²⁺ channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Ca_v2.3 R-type Ca²⁺ channel which exhibits an intriguing role in ictogenesis and seizure propagation. Ca_v2.3 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.

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 Ca_v2.3 R-type Ca²⁺ channels and point to recent findings in the proictogenic and proneuroapoptotic role of Ca_v2.3 R-type VGCCs in generalized convulsive tonic–clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity.

Development of novel Ca_v2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.