Calcium Channels - A Brief Introduction


Voltage-gated calcium channels are membrane proteins in electrically excitable cells. They open if these cells are excited by a depolarizing stimulus. The membrane depolarization is recognized by voltage sensors in the protein and converted to a conformational change of the channel protein which then opens the ion pore and allows calcium ions to flow into the cell from the extracellular space (concentration about 1 mM) along a 10,000 - fold concentration gradient.

Intracellular free calcium concentrations (basal: 0.0001 mM) then rise and activate a number of intracellular calcium dependent processes which trigger (or modulate) cellular responses. This allows e.g. muscle cells to respond to depolarization with contraction (regulate vascular resistance and cardiac contraction), pancreatic β - cells to release insulin (lower blood glucose), neurons to release neurotransmitters (such as e.g. GABA and glutamate in central neurons and acetylcholine at the neuromuscular junction) and to change functional properties of neurons (important for memory and learning and maintainance of normal neuronal activity).

Remarkably, the channel is able to selectively recognize and conduct calcium ions although the majority of ions in the extracellular solution are sodium (about 150 mM), potassium (about 4 mM), and chloride (100 mM). This is achieved by a tricky mechanism in which the channel forms a "sticky" site for calcium (containing negatively charged amino acid side chains) at the outer mouth of the pore. Positively charged calcium ions must bind to this site before permeation through the pore. Thus this site serves as "selectivity filter".


  Calcium channel structure: (left panel)
Most voltage-gated calcium channels consist of several proteins non-covalently associated with each other. They are termed α1, α2-δ , β and γ subunits. α2 and γ carry complex carbohydrate moieties (glycoproteins). The channel pore itself is formed only by α1. More recently additional proteins were found to closely interact with the calcium channel complex, such as for example calmodulin. Such interaction partners modulate channel gating and can control surface expression. Protein interaction partners may also carry information plasmalemmal calcium channel activity further into the cell, for example by activation of the MAP-kinase pathway in neurons. Other than shown in this Figure, the α2-δ subunit (green) is believed to be completely extracellular and anchored to the membrane via a GPI-anchor.


α1-subunit structure: (right panel)
α1 subunit consists of about 2000 amino acid residues (molecular mass about 240,000 dalton) and carries all the structural features required for a calcium - selective, voltage-activated channel: the voltage sensors (positive charges in S4 helices), the selectivity filter (glutamate rgions in the S5 - S6 linkers, illustrated in red), and the ion conducting pathway (comprised by the S5 + S5 - S6 - linker + S6 in the four repeats illustrated in blue). N, N-terminus, C, C - terminus of protein. The inset shows the possible arrangement of the transmembranne helices around a calcium-selective pore. We already can guess the 3D structure of α1-subunits at high resolution based on X-ray structures of structurally related bacterial and mammalian Na+- and K+-channels.
 

Interested in more calcium channel facts? Check these reviews.


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