Psychology Wiki

Voltage-dependent calcium channel

Revision as of 23:50, January 3, 2010 by Dr Joe Kiff (Talk | contribs)

34,200pages on
this wiki

Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual differences | Personality | Philosophy | Social |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |

Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)

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.


Voltage-dependent calcium channels are formed as a complex of several different subunits: α1, α2, β, γ, and δ. The α1 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 ω-conotoxins, the residual R-type channel involved in processes in the brain and muscle, the closely related P/Q-type channel blocked by ω-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.

α 1 subunit

The α 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 α-helices each. The α 1 subunit forms the Ca2+ selective pore which contains voltage sensing machinery and the drug/toxin binding sites. There are multiple α 1 subunits that have been classified.

β subunit

The intracellular β 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 β subunit binds to the α 1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the β subunit.

It is hypothesized that the cytosolic β subunit has the initial role of stabilizing the final α1 subunit conformation and delivering it to cell membrane by its ability to mask an endoplasmic reticulum retention signal in the α1 subunit. Bichet et al. discovered that the endoplasmic retention brake was contained in the I-II loop in the α1 subunit that becomes masked when the β subunit binds. Therefore the β subunit functions initially to regulate the current density by controlling the amount of α subunit expressed at the cell membrane.

In addition to this initial role, the β subunit has the added important functions of regulating the activation/ inactivation kinetics and increasing the peak amplitude in current of the α1 subunit pore once it aids in the delivery of the α1 subunit to the membrane. Singer et al. first discovered that the β subunit had effects on the kinetics of the cardiac α1C in Xenopus oocytes co-expressed with β subunits. Later studies by Walker and De Waard further showed that the β subunit acted as an important modulator of channel electrophysiological properties.

Until very recently, the interaction between a highly conserved 18 AA region on the α1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain) and a region on the GK domain of the β subunit (Alpha Interaction Domain Binding Pocket) was thought to be solely responsible for the regulatory effects by the β subunit. Recently it has been discovered that the SH3 domain of the β subunit also gives added regulatory effects on channel function, opening the possibility of the β subunit having multiple regulatory interactions with the α1 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 α1 subunit linker when mutations/deletions to the AID region gave the same expression at the plasma membrane and did not increase the current amplitudes.

α2δ subunit

The α2δ 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 α2δ subunit arises due to alternative splicing of their gene. The α2 is the extracellular glycosylated subunit that interacts the most with the α1 subunit. The δ 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 α2δ enhances the level of expression of the α1 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 α2δ 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.

γ subunit

The γ subunit is associated with only some of the HVGCC complexes. The γ subunit glysoprotein (33 kDa) is composed of four transmembrane spanning helices. The γ subunits does not affect trafficking and for the most part is not required to regulate the channel complex. The γ1 subunit is associated with skeletal muscle while the γ2 and γ3 are associated with the P/Q and N-type channels.

Muscle Physiology

When a smooth muscle cell is depolarized, it causes opening of the voltage-gated, or L-type, calcium channels.[1][2] Depolarization may be brought about by stretching of the cell, agonist-binding its G protein-coupled receptor (GPCR), or autonomic nervous system stimulation. Opening of the L-type calcium channel causes influx of extracellular Ca2+, which then binds calmodulin. The activated calmodulin molecule activates myosin light-chain kinase (MLCK), which phosphorylates the myosin in thick filaments. Phosphorylated myosin is able to form crossbridges with actin thin filaments, and the smooth muscle fiber (i.e., cell) contracts via the sliding filament mechanism. (See reference[1] for an illustration of the signaling cascade involving L-type calcium channels in smooth muscle).

L-type calcium channels are also enriched in the t-tubules of striated muscle cells, i.e., skeletal and cardiac myofibers. When these cells are depolarized, the L-type calcium channels open as in smooth muscle. In skeletal muscle, the actual opening of the channel, which is mechanically gated to a calcium-release channel (a.k.a. ryanodine receptor, or RYR) in the sarcoplasmic reticulum (SR), causes opening of the RYR. In cardiac muscle, opening of the L-type calcium channel permits influx of calcium into the cell. The calcium binds to the calcium release channels (RYRs) in the SR, opening them; this phenomenon is called "calcium-induced calcium release," or CICR. However the RYRs are opened, either through mechanical-gating or CICR, Ca2+ is released from the SR and is able to bind to troponin C on the actin filaments. The muscles then contract through the sliding filament mechanism, causing shortening of sarcomeres and muscle contraction.

See also


  1. 1.0 1.1 Webb RC (2003). Smooth muscle contraction and relaxation. Adv Physiol Educ 27 (1-4): 201–6.
  2. Alberts, Bruce; Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell, 4th, New York, NY: Garland Science.

External links

This page uses Creative Commons Licensed content from Wikipedia (view authors).

Around Wikia's network

Random Wiki