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 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.

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 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.

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

Keywords: Absence epilepsy; Afterdepolarisation; Ictal discharges; Low-threshold Ca2+ spike; Plateau potentials; R-type; Seizure.

Fig. (1)

Structural buildup of voltage-gated Ca²⁺ channel complexes. Voltage-gated Ca²⁺ channels are composed of a central pore-forming and ion-conducting α₁ subunit as well a variable subset of auxiliary subunits, including α₂δ, β and γ-subunits. The β-subunit is located intracellularly whereas the γ and δ subunits are placed within the plasma membrane. The α₂ subunit is covalently bound to the δ subunit via a disulfide bond and localized extracellularly. Both the Ca_v-α₁ subunits as well as the auxiliary subunits are important drug targets (reprinted from [68]).

Fig. (2)

Functional interaction of divalent heavy metal ions (Zn²⁺) and various ion channels and transporters within the hippocampal CA3 region. Mossy fiber terminals carry both Zn²⁺ and glutamate containing vesicles. Upon presynaptic excitation, glutamate and zinc are released into the synaptic cleft. Zn²⁺ exerts numerous effects on AMPA and NMDA receptors, GABA receptors and transporters. Voltage-gated Ca²⁺ channels, particularly Ca_v2.3 VGCCs turned out to be of central relevance. Note that both Ca²⁺ and Zn²⁺ that enter the cell exert complex effects on intracellular signal transduction cascades (reprinted from [259]).

Fig. (3)

Functional implications of Ca_v2.3 R-type VGCC in cellular epileptiform activity, excitotoxicity and thetagenesis. Ca_v2.3 mediated Ca²⁺ influx triggers varies intracellular cascades. One cascade mediates the activation of cyclic-nucleotide gated channels leading to plateau potentials and superimposed bursting. Associated hyperexcitability and Ca²⁺ overload can result in excitotoxicity and neuronal apoptosis. Note that Ca_v2.3 Ca²⁺ channels are modulated by muscarinic signaling. The G α_q11, DAG and PKC pathway was reported to be associated with thetagenesis as well (reprinted from [260]).