Calcium Channels


Calcium channels are plasma membrane proteins containing calcium‐selective pores that are opened by depolarisation of the membrane voltage. They produce depolarisation‐induced calcium entry in neurons, muscle and other excitable cells, as well as some nonexcitable cells. Functions mediated by calcium channels include contraction of muscle, release of neurotransmitters and hormones by neurons and neuroendocrine cells, and control of gene transcription. Calcium channels are multi‐subunit proteins encoded by many separate genes, and the resulting proteins often govern distinct functional roles within a given cell type. They are targets for modulation by many intracellular signalling pathways including G proteins and phosphorylation. Calcium channels play pivotal roles in many human diseases, particularly of the cardiac and nervous systems, including pain, seizure, hypertension and migraine. Pharmacological blockers for some types of calcium channels are known, including clinically used drugs for hypertension and pain. In some cases such calcium channel blockers are highly selective for specific types of calcium channels, but there is great potential for developing more selective and more potent drugs targeting calcium channels.

Key Concepts:

  • Voltage‐gated calcium channels are proteins that selectively conduct calcium ions from the outside to the inside of the cell in response to a change in transmembrane voltage from more to less negative.

  • At the cellular level, calcium channels are a major link between electrical signalling and intracellular biochemical signalling. Calcium channel function is modulated strongly by a variety of intracellular enzymes and signalling pathways.

  • Many genes encode calcium channels. Different subtypes often carry out distinct physiological functions, via distinct cellular locations and biophysical properties.

  • Calcium channels govern physiological functions including neurotransmitter and hormone release, muscle contraction and the regulation of gene expression.

  • Calcium channel dysfunction contributes to diseases including cardiac arrhythmia, hypertension, chronic pain, epilepsy and migraine. They are under investigation for their role in diseases including autism, schizophrenia and bipolar spectrum disorder.

Keywords: ion channels; voltage‐dependent gating; ionic selectivity; action potential; dihydropyridines; migraine; pain; β‐cell; ziconotide; pregabalin

Figure 1.

Voltage‐dependent activation of calcium channels. (a) Voltage‐clamp recording of calcium channel currents in a whole‐cell recording from a rat cerebellar Purkinje neuron. Intracellular and extracellular solutions were chosen to block currents through voltage‐dependent sodium and potassium channels and thus isolate current carried by voltage‐dependent calcium channels (mainly P‐type channels). Internal solution (mmol L−1): CsCl, 56; CsF, 68; MgCl2, 2.2; ethylene glycol bis(β‐aminoethyl ether)‐N,N‐tetraacetic acid (EGTA) , 4.5; Hepes, 9; MgATP, 4; creatine phosphate, 14 and guanosine triphosphate (GTP) 0.3 (pH 7.4). External solution (in mmol L−1): BaCl2, 2; TEACl, 160; Hepes, 10 (pH 7.4), with tetrodotoxin 600 nmol L−1. The calcium channels are all closed at the holding potential of −80 mV. Depolarising the membrane to −50 mV is not sufficient to open the channels, but on depolarisation to −10 mV, an inward current activates. The current is carried by barium ions flowing into the cell through the calcium channels opened as a result of the depolarisation. The cell contains approximately 60 000 channels, of which approximately 30 000 are simultaneously open during the step to −10 mV. On stepping the membrane voltage back to −60 mV, the current through the channels becomes instantaneously larger because the more negative intracellular voltage exerts a larger driving force on the barium ions. The calcium channels then close over the next several milliseconds, resulting in the decline of the current. The recording was made at 10°C to slow the kinetics of channel gating. (b) Voltage‐dependence of channel activation during steps like those in (a). The relative activation was quantified by the size of the ‘tail current’ at −60 mV immediately following the test voltage, normalised with respect to that for a test voltage of 0 mV. Recording by S. I. McDonough.

Figure 2.

Block and enhancement of L‐type calcium channel currents by different dihydropyridine drug molecules. (a) Voltage‐clamp recording of calcium channel currents in a whole‐cell recording from a stably transfected cell expressing cloned Cav1.2 (cardiac L‐type) channels. Application of 1 μmol L−1 nimodipine blocks almost all of the current elicited by a step to −10 mV. (b) Application (in a different cell) of the dihydropyridine ‘calcium channel agonist’ Bay K 8644 produces enhancement of the current elicited by a step to −20 mV. Note that depolarisation is still required for activation of the channels. Internal solution (in mmol L−1): CsCl, 113; MgCl2, 4; EGTA, 9; Hepes, 9; MgATP, 4; creatine phosphate, 14 and GTP, 0.3 (pH 7.4). External solution (in mmol L−1): BaCl2, 2; TEACl, 160; Hepes, 10 (pH 7.4), with tetrodotoxin, 600 nmol L−1. Recording by S. I. McDonough using a cell line constructed by Dr Yasuo Mori.

Figure 3.

Single‐channel currents through L‐type calcium channels in a bullfrog cardiac ventricular muscle cell. Recording was made in the cell‐attached configuration. The resting potential of the cell was set to zero by a high‐potassium bath solution (128 mmol L−1potassium methanesulfonate, 1.6 mmol L−1MgCl2, 0.08 mmol L−1 EGTA, 8 mmol L−1Hepes, pH adjusted to 7.4 with KOH) designed to mimic the ionic composition of normal intracellular solution. The pipette solution was 110 mmol L−1BaCl2, 10 mmol L−1Hepes, 100 mmol L−1ethylenediaminetetraacetic acid (EDTA), 3 μmol L−1tetrodotoxin (TTX), 5 μmol L−1 Bay K 8644, pH adjusted to 7.4 with tetraethylammonium chloride. The magnitude of current through open calcium channels was enhanced by the high concentration of barium (which is more permeant than calcium) and the open probability of the channels was enhanced by Bay K 8644. The voltage across the patch was controlled by changing the voltage in the pipette. Channels are closed at −70 mV and open in a stochastic manner when the patch is depolarised to −20 mV. Records are shown for four 300 ms steps of voltage from −70 to −20 mV. The stochastic behaviour of the channel is different in each trial. Recording by A. C. Jackson.

Figure 4.

Different inactivation kinetics of T‐type calcium current and P‐type calcium current in Purkinje neurons. T‐type current (left) is activated by a voltage step from −90 to −20 mV, but then inactivates even though the voltage step is maintained. In contrast, P‐type current (right) displays little inactivation during the step to −20 mV. Both currents were recorded in mouse cerebellar Purkinje neurons at 35°C. Internal solution (in mmol L−1): CsCl, 56; CsF, 68; MgCl2, 2.2; EGTA, 4.5; Hepes, 9; MgATP, 4; creatine phosphate, 14 and GTP, 0.3 (pH 7.4). External solution (in mmol L−1): TEACl, 160; BaCl2, 5; Hepes, 10 (pH 7.4), with tetrodotoxin, 600 nmol L−1. In the recording on the left, T‐type current was isolated by blocking L‐type, P‐type and N‐type currents with the combination of 1 μmol L−1 nimodipine and 10 μmol L−1 ω‐conotoxin MVIIC added to the external solution. In the recording on the right, T‐type current was eliminated by the holding potential of −55 mV, which inactivates T‐type current but not P‐type current. Small components of L‐type and N‐type current may also be present. Recording by S. I. McDonough.



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Further Reading

Aidley DJ and Stanfield PR (1996) Ion Channels: Molecules in Action. Cambridge, UK: Cambridge University Press.

Alexander SPH, Mathie A and Peters JA (2010) Guide to Receptors and Channels (GRAC), 4th edition. British Journal of Pharmacology 158(suppl. 1): S1–S254.

Ashcroft F (2000) Ion Channels in Disease. London: Academic Press.

McDonough SI (ed.) (2004) Calcium Channel Pharmacology. New York: Kluwer/Academic/Plenum Publishing.

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Bean, Bruce P, and McDonough, Stefan I(Sep 2010) Calcium Channels. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000028.pub2]