Calcium Channels

Abstract

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.

close

References

Ashcroft FM (1991) Ca2+ channels and excitation‐contraction coupling. Current Opinion in Cell Biology 3(4): 671–675.

Barclay J, Balaguero N, Mione M et al. (2001) Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. Journal of Neuroscience 21(16): 6095–6104.

Bauer CS, Nieto‐Rostro M, Rahman W et al. (2009) The increased trafficking of the calcium channel subunit alpha2delta‐1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. Journal of Neuroscience 29(13): 4076–4088.

Bers DM (2002) Cardiac excitation‐contraction coupling. Nature 415(6868): 198–205.

Burgess DL, Jones JM, Meisler MH and Noebels JL (1997) Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 88(3): 385–392.

Carbone E and Lux HD (1984) A low voltage‐activated, fully inactivating Ca channel in vertebrate sensory neurones. Nature 310(5977): 501–502.

Catterall WA (1999) Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter release. Annals of the New York Academy of Science 868: 144–159.

Catterall WA (2000) Structure and regulation of voltage‐gated Ca2+ channels. Annual Review of Cell and Developmental Biology 16: 521–555.

Catterall WA and Few AP (2008) Calcium channel regulation and presynaptic plasticity. Neuron 59(6): 882–901.

Catterall WA, Striessnig J, Snutch TP and Perez‐Reyes E (2003) International union of pharmacology. XL. Compendium of voltage‐gated ion channels: calcium channels. Pharmacological Reviews 55(4): 579–581.

Chaudhuri D, Issa JB and Yue DT (2007) Elementary mechanisms producing facilitation of Cav2.1 (P/Q‐type) channels. Journal of General Physiology 129(5): 385–401.

Chen L, Chetkovich DM, Petralia RS et al. (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408(6815): 936–943.

Chen YH, Li MH, Zhang Y et al. (2004) Structural basis of the alpha1‐beta subunit interaction of voltage‐gated Ca2+ channels. Nature 429(6992): 675–680.

Dai S, Hall DD and Hell JW (2009) Supramolecular assemblies and localized regulation of voltage‐gated ion channels. Physiological Reviews 89(2): 411–452.

DeMaria CD, Soong TW, Alseikhan BA, Alvania RS and Yue DT (2001) Calmodulin bifurcates the local Ca2+ signal that modulates P/Q‐type Ca2+ channels. Nature 411(6836): 484–489.

Dietrich D, Kirschstein T, Kukley M et al. (2003) Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron 39(3): 483–496.

Dolphin AC (2003) G protein modulation of voltage‐gated calcium channels. Pharmacological Reviews 55(4): 607–627.

Dolphin AC (2009) Calcium channel diversity: multiple roles of calcium channel subunits. Current Opinion in Neurobiology 19(3): 237–244.

Ellinor PT, Yang J, Sather WA, Zhang JF and Tsien RW (1995) Ca2+ channel selectivity at a single locus for high‐affinity Ca2+ interactions. Neuron 15(5): 1121–1132.

Ertel EA, Campbell KP, Harpold MM et al. (2000) Nomenclature of voltage‐gated calcium channels. Neuron 25(3): 533–535.

Field MJ, Cox PJ, Stott E et al. (2006) Identification of the alpha2‐delta‐1 subunit of voltage‐dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proceedings of the National Academy of Sciences of the USA 103(46): 17537–17542.

Fuller‐Bicer GA, Varadi G, Koch SE et al. (2009) Targeted disruption of the voltage‐dependent calcium channel alpha2/delta‐1‐subunit. American Journal of Physiology 297(1): H117–H124.

Gray AC, Raingo J and Lipscombe D (2007) Neuronal calcium channels: splicing for optimal performance. Cell Calcium 42(4–5): 409–417.

Green EK, Grozeva D, Jones I et al. (2009) The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Molecular Psychiatry doi: 10.1038/mp.2009.49.

Hashimoto K, Fukaya M, Qiao X et al. (1999) Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. Journal of Neuroscience 19(14): 6027–6036.

Hedley PL, Jorgensen P, Schlamowitz S et al. (2009) The genetic basis of Brugada syndrome: a mutation update. Human Mutation 30(9): 1256–1266.

Hendrich J, Van Minh AT, Heblich F et al. (2008) Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proceedings of the National Academy of Sciences of the USA 105(9): 3628–3633.

Herlitze S, Garcia DE, Mackie K et al. (1996) Modulation of Ca2+ channels by G‐protein beta gamma subunits. Nature 380(6571): 258–262.

Hess P and Tsien RW (1984) Mechanism of ion permeation through calcium channels. Nature 309(5967): 453–456.

Hille B (2001) Ion Channels of Excitable Membranes. Sunderland, MA: Sinauer Associates.

Huguenard JR (1996) Low‐threshold calcium currents in central nervous system neurons. Annual Review of Physiology 58: 329–348.

Ikeda SR (1996) Voltage‐dependent modulation of N‐type calcium channels by G‐protein beta gamma subunits. Nature 380(6571): 255–258.

Jing X, Li DQ, Olofsson CS et al. (2005) CaV2.3 calcium channels control second‐phase insulin release. Journal of Clinical Investigation 115(1): 146–154.

Letts VA, Felix R, Biddlecome GH et al. (1998) The mouse stargazer gene encodes a neuronal Ca2+‐channel gamma subunit. Nature Genetics 19(4): 340–347.

Lipscombe D, Helton TD and Xu W (2004) L‐type calcium channels: the low down. Journal of Neurophysiology 92(5): 2633–2641.

Mangoni ME, Couette B, Bourinet E et al. (2003) Functional role of L‐type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proceedings of the National Academy of Sciences of the USA 100(9): 5543–5548.

Mangoni ME and Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiological Reviews 88(3): 919–982.

Marks AR (1997) Intracellular calcium‐release channels: regulators of cell life and death. American Journal of Physiology 272(Part 2): H597–H605.

Martin SW, Butcher AJ, Berrow NS et al. (2006) Phosphorylation sites on calcium channel alpha1 and beta subunits regulate ERK‐dependent modulation of neuronal N‐type calcium channels. Cell Calcium 39(3): 275–292.

Miljanich GP (2004) Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Current Medicinal Chemistry 11(23): 3029–3040.

Mintz IM, Venema VJ, Swiderek KM et al. (1992) P‐type calcium channels blocked by the spider toxin omega‐Aga‐IVA. Nature 355(6363): 827–829.

Morad M and Soldatov N (2005) Calcium channel inactivation: possible role in signal transduction and Ca2+ signaling. Cell Calcium 38(3–4): 223–231.

Newcomb R, Szoke B, Palma A et al. (1998) Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas. Biochemistry 37(44): 15353–15362.

Olivera BM, Rivier J, Clark C et al. (1990) Diversity of conus neuropeptides. Science 249(4966): 257–263.

Ophoff RA, Terwindt GM, Vergouwe MN et al. (1996) Familial hemiplegic migraine and episodic ataxia type‐2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87(3): 543–552.

Perez‐Reyes E (2003) Molecular physiology of low‐voltage‐activated T‐type calcium channels. Physiological Reviews 83(1): 117–161.

Perez‐Reyes E (2006) Molecular characterization of T‐type calcium channels. Cell Calcium 40(2): 89–96.

Pietrobon D (2005) Function and dysfunction of synaptic calcium channels: insights from mouse models. Current Opinion in Neurobiology 15(3): 257–265.

Platzer J, Engel J, Schrott‐Fischer A et al. (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L‐type Ca2+ channels. Cell 102(1): 89–97.

Pouille F, Cavelier P, Desplantez T et al. (2000) Dendro‐somatic distribution of calcium‐mediated electrogenesis in Purkinje cells from rat cerebellar slice cultures. Journal of Physiology 527(Part 2): 265–282.

Regehr WG and Mintz IM (1994) Participation of multiple calcium channel types in transmission at single climbing fiber to Purkinje cell synapses. Neuron 12(3): 605–613.

Sabatini BL and Regehr WG (1999) Timing of synaptic transmission. Annual Review of Physiology 61: 521–542.

Spafford JD and Zamponi GW (2003) Functional interactions between presynaptic calcium channels and the neurotransmitter release machinery. Current Opinion in Neurobiology 13(3): 308–314.

Splawski I, Timothy KW, Sharpe LM et al. (2004) Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119(1): 19–31.

Strom SP, Stone JL, Ten Bosch JR et al. (2009) High‐density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Molecular Psychiatry doi: 10.1038/mp.2009.41.

Strom TM, Nyakatura G, Apfelstedt‐Sylla E et al. (1998) An L‐type calcium‐channel gene mutated in incomplete X‐linked congenital stationary night blindness. Nature Genetics 19(3): 260–263.

Triggle DJ (1999) The pharmacology of ion channels: with particular reference to voltage‐gated Ca2+ channels. European Journal of Pharmacology 375(1–3): 311–325.

Uebele VN, Gotter AL, Nuss CE et al. (2009) Antagonism of T‐type calcium channels inhibits high‐fat diet‐induced weight gain in mice. Journal of Clinical Investigation 119(6): 1659–1667.

Van Petegem F, Clark KA, Chatelain FC and Minor DL Jr (2004) Structure of a complex between a voltage‐gated calcium channel beta‐subunit and an alpha‐subunit domain. Nature 429(6992): 671–675.

Weissgerber P, Held B, Bloch W et al. (2006) Reduced cardiac L‐type Ca2+ current in Ca(V)beta2–/– embryos impairs cardiac development and contraction with secondary defects in vascular maturation. Circulation Research 99(7): 749–757.

Yang SN and Berggren PO (2006) The role of voltage‐gated calcium channels in pancreatic beta‐cell physiology and pathophysiology. Endocrine Reviews 27(6): 621–676.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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