Voltage-dependent calcium channel

Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells (neurons, glial cells, muscle cells, etc.) with a permeability to the ion Ca2+, which plays a role in the membrane potential. VDCCs are involved in the release of neurotransmitters and hormones, muscular contraction, excitability of neurons and gene expression.

Types of VDCC

 * HVA (hight-voltage activated)
 * L-type
 * N-type
 * P/Q-type
 * R-type (intermediate voltage activated)
 * T-type (low voltage activated)

Therapeutic options
L-type calcium channel blockers are used as antiarrhythmics or antihypertonics, depending on whether the drugs has higher affiniy to the heart (like verapamil) or to the vessels (nifedipine). T-type calcium channel blockers are used primary as antiepileptics, but also as anaesthetics or antipsychotics.

Structure
Voltage-dependent calcium channels are formed as a complex of several different subunits: &#945;1, &#945;2, &#946;, &#947;, and &#948;. The &#945;1 subunit is the one that decides most of the channel properties.

High voltage gated calcium channels
High voltage gated calcium channels (HVGCCs) are structurally homologous among varying types and are differentiated according to their physiological roles and/or inhibition by specific toxins. High voltage gated calcium channels include the neural N-type channel blocked by &#969;-conotoxins, the residual R-type channel involved in processes in the brain and muscle, the closely related P/Q-type channel blocked by &#969;-agatoxins, and the dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle and for hormone secretion in endocrine cells.

&#945; 1 subunit
The &#945; 1 subunit pore (190 kDa) is the primary subunit necessary for channel functioning in the HVGCC, and consists of the characteristic four homologous I-IV domains containing six transmembrane &#945;-helices each. The &#945; 1 subunit forms the Ca2+ selective pore which contains voltage sensing machinery and the drug/toxin binding sites. There are multiple &#945; 1 subunits that have been classified.

&#946; subunit
The intracellular &#946; subunit (55 kDa) is an intracellular MAGUK-like protein (Membrane Associated Guanylate Kinase) containing a guanylate kinase (GK) domain and an SH3 (src homology 3) domain. The guanylate kinase domain of the &#946; subunit binds to the &#945; 1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the &#946; subunit.

It is hypothesized that the cytosolic &#946; subunit has the initial role of stabilizing the final &#945;1 subunit conformation and delivering it to cell membrane by its ability to mask an endoplasmic reticulum retention signal in the &#945;1 subunit. Bichet et al. discovered that the endoplasmic retention brake was contained in the I-II loop in the &#945;1 subunit that becomes masked when the &#946; subunit binds. Therefore the &#946; subunit functions initially to regulate the current density by controlling the amount of &#945; subunit expressed at the cell membrane.

In addition to this initial role, the &#946; subunit has the added important functions of regulating the activation/ inactivation kinetics and increasing the peak amplitude in current of the &#945;1 subunit pore once it aids in the delivery of the &#945;1 subunit to the membrane. Singer et al. first discovered that the &#946; subunit had effects on the kinetics of the cardiac &#945;1C in Xenopus oocytes co-expressed with &#946; subunits. Later studies by Walker and De Waard further showed that the &#946; subunit acted as an important modulator of channel electrophysiological properties.

Until very recently, the interaction between a highly conserved 18 AA region on the &#945;1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain) and a region on the GK domain of the &#946; subunit (Alpha Interaction Domain Binding Pocket) was thought to be solely responsible for the regulatory effects by the &#946; subunit. Recently it has been discovered that the SH3 domain of the &#946; subunit also gives added regulatory effects on channel function, opening the possibility of the &#946; subunit having multiple regulatory interactions with the &#945;1 subunit pore. Furthermore, it was discovered that the AID does not contain the endoplasmic reticulum retention signal and is most likely located in other regions of the I-II &#945;1 subunit linker when mutations/deletions to the AID region gave the same expression at the plasma membrane and did not increase the current amplitudes.

&#945;2&#948; subunit
The &#945;2&#948; are two subunits that are linked to each other via a disulfide bond and have a molecular weight of 170 kDa. The diversity of each &#945;2&#948; subunit arises due to alternative splicing of their gene. The &#945;2 is the extracellular glycosylated subunit that interacts the most with the &#945;1 subunit. The &#948; subunit has a single transmembrane region with a short intracellular portion which serves to anchor the protein in the plasma membrane.

Co-expression of the &#945;2&#948; enhances the level of expression of the &#945;1 subunit and causes an increase in current amplitude, faster activation and inactivation kinetics and a hyperpolarizing shift in the voltage dependence of inactivation. Some of these affects are observed in the absence of the beta subunit whereas in other cases the co-expression of beta is required.

The &#945;2&#948; subunit on the N-type Ca++ channel appears to be the binding site for at least two anticonvulsant drugs, gabapentin (Neurontin®) and pregabalin (Lyrica®), that also find use in treating chronic neuropathic pain.

&#947; subunit
The &#947; subunit is associated with only some of the HVGCC complexes. The &#947; subunit glysoprotein (33 kDa) is composed of four transmembrane spanning helices. The &#947; subunits does not affect trafficking and for the most part is not required to regulate the channel complex. The &#947;1 subunit is associated with skeletal muscle while the &#947;2 and &#947;3 are associated with the P/Q and N-type channels.