L-type calcium channel
Calcium channel, voltage-dependent | |
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![]() Crystallographic structure of the L-type calcium channel complex (subunits | |
Identifiers | |
Symbol | Calcium channel, voltage-dependent |
![](https://upload.wikimedia.org/wikipedia/commons/thumb/0/0e/L-type_D-subtype_CaV1.3_calcium_channel_CACNA1D_in_human_adrenal_zona_glomerulosa.jpg/200px-L-type_D-subtype_CaV1.3_calcium_channel_CACNA1D_in_human_adrenal_zona_glomerulosa.jpg)
![](https://upload.wikimedia.org/wikipedia/commons/thumb/5/59/General_L-type_calcium_channel.jpg/308px-General_L-type_calcium_channel.jpg)
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.[2] "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.
L-type calcium channels are responsible for the excitation-contraction coupling of skeletal, smooth, cardiac muscle, and for aldosterone secretion in endocrine cells of the adrenal cortex.[1] They are also found in neurons, and with the help of L-type calcium channels in endocrine cells, they regulate neurohormones and neurotransmitters. They have also been seen to play a role in gene expression, mRNA stability, neuronal survival, ischemic-induced axonal injury, synaptic efficacy, and both activation and deactivation of other ion channels.[3]
In cardiac myocytes, the L-type calcium channel passes inward Ca2+ current (ICaL) and triggers calcium release from the sarcoplasmic reticulum by activating ryanodine receptor 2 (RyR2) (calcium-induced-calcium-release).[4] Phosphorylation of these channels increases their permeability to calcium and increases the contractility of their respective cardiac myocytes.
L-type calcium channel blocker drugs are used as cardiac antiarrhythmics or antihypertensives, depending on whether the drugs have higher affinity for the heart (the phenylalkylamines, like verapamil), or for the blood vessels (the dihydropyridines, like nifedipine).[5]
In skeletal muscle, there is a very high concentration of L-type calcium channels, situated in the T-tubules. Muscle depolarization results in large gating currents, but anomalously low calcium flux, which is now explained by the very slow activation of the ionic currents. For this reason, little or no Ca2+ passes across the T-tubule membrane during a single action potential.
History
[edit]In 1953, Paul Fatt and Bernard Katz discovered voltage gated calcium channels in crustacean muscle. The channels exhibited different activation voltages and calcium conducting properties and were thus separated into High Voltage Activating channels (HVA) and Low Voltage Activating channels (LVA). After further experimentation, it was found that HVA channels were blocked by derivatives of 1,4-dihydropyridine (DHPs).[6] Using DHPs, it was found that HVA channels were specific to certain tissues and reacted differently, which led to further categorization of the HVA channels into L-type, P-type, and N-type.[3] L-type calcium channels were peptide sequenced and it was found that there were 4 kinds of L-type calcium channels:
Structure
[edit]L-type Calcium Channels contain 5 different subunits, the
The
The
The
The
Mechanism
[edit]Opening of the pore in L-type calcium channels takes place in the
The most predominant way of autoinhibition of L-type calcium channels is with the Ca2+/Cam complex.[11] As the pore opens and causes an influx of calcium, calcium binds to calmodulin and then interacts with the loop that connects the adjacent EF-hand motifs and causes a conformational change in the EF-hand motif so it interacts with the pore to cause quick inhibition in the channel.[6] It is still debated on where and how the pore and EF-hand interact. Hydrophobic pockets in the Ca2+/Cam complex will also bind to three sections of the IQ domain known as the “aromatic anchors”.[11] The Ca2+/Cam complex has a high affinity towards L-type calcium channels, allowing it to get blocked even when there are low amounts of calcium present in the cell. The pore eventually closes as the cell repolarizes and causes a conformational change in the channel to put it in the closed conformation.
Inhibition and modulation
[edit]One of the most recognized characteristics of the L-type calcium channel is its unique sensitivity to 1,4-dihydropyridines (DHPs).[3] Unlike other voltage gated calcium channels, L-type calcium channels are resistant to ⍵-CT X (GVIA) and ⍵-AG A (IVA) inhibitory drugs.[3]
A well observed form of modulation is due to alternative splicing. A common form of modulation from alternative splicing is the C-terminal modulator (CTM). It has a positively charged
Alternative splicing is also seen on the
L-type calcium channels are also modulated by G protein-coupled receptors and the adrenergic nervous system.[6] Protein Kinase A (PKA) activated by a G protein-coupled receptors cascade can phosphorylate L-type calcium channels, after channels form a signaling complex with A-Kinase-Anchoring proteins (AKAPs), to increase calcium current through the channel, increasing the open-state probability, and an accelerated recovery period. Activated Phospholipase C (PLC) from G protein-coupled receptors can breakdown polyphosphoinositides to decrease the channel's calcium current by 20%-30%.[7]
The adrenergic nervous system has been seen to modulate L-type calcium channels by cleaving the C-terminal fragment when the
![](https://upload.wikimedia.org/wikipedia/commons/thumb/e/e0/Alphasubunit_sodium_channel.png/220px-Alphasubunit_sodium_channel.png)
Genes
[edit]See also
[edit]References
[edit]- ^ a b Felizola SJ, Maekawa T, Nakamura Y, Satoh F, Ono Y, Kikuchi K, et al. (October 2014). "Voltage-gated calcium channels in the human adrenal and primary aldosteronism". The Journal of Steroid Biochemistry and Molecular Biology. 144 Pt B (part B): 410–416. doi:10.1016/j.jsbmb.2014.08.012. PMID 25151951. S2CID 23622821.
- ^ Rossier MF (2016). "T-Type Calcium Channel: A Privileged Gate for Calcium Entry and Control of Adrenal Steroidogenesis". Frontiers in Endocrinology. 7: 43. doi:10.3389/fendo.2016.00043. PMC 4873500. PMID 27242667.
- ^ a b c d e f g Lipscombe D, Helton TD, Xu W (November 2004). "L-type calcium channels: the low down". Journal of Neurophysiology. 92 (5): 2633–2641. doi:10.1152/jn.00486.2004. PMID 15486420.
- ^ Yamakage M, Namiki A (February 2002). "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review". Canadian Journal of Anaesthesia. 49 (2): 151–164. doi:10.1007/BF03020488. PMID 11823393.
- ^ Hughes A (2017). "Calcium channel blockers". In Bakris G, Sorrentino M (eds.). Hypertension: a companion to Braunwald's heart disease (Third ed.). Philadelphia, PA: Elsevier Health Sciences. pp. 242–253. ISBN 9780323508766. OCLC 967938982.
- ^ a b c d e f g Dolphin AC (October 2018). "Voltage-gated calcium channels: their discovery, function and importance as drug targets". Brain and Neuroscience Advances. 2: 2398212818794805. doi:10.1177/2398212818794805. PMC 6179141. PMID 30320224.
- ^ a b c d e f Striessnig J, Pinggera A, Kaur G, Bock G, Tuluc P (March 2014). "L-type Ca2+ channels in heart and brain". Wiley Interdisciplinary Reviews. Membrane Transport and Signaling. 3 (2): 15–38. doi:10.1002/wmts.102. PMC 3968275. PMID 24683526.
- ^ a b Bodi I, Mikala G, Koch SE, Akhter SA, Schwartz A (December 2005). "The L-type calcium channel in the heart: the beat goes on". The Journal of Clinical Investigation. 115 (12): 3306–3317. doi:10.1172/JCI27167. PMC 1297268. PMID 16322774.
- ^ "Voltage-gated calcium channels | Introduction | BPS/IUPHAR Guide to PHARMACOLOGY". www.guidetopharmacology.org. Retrieved 2019-11-28.
- ^ Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (December 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacological Reviews. 57 (4): 411–425. doi:10.1124/pr.57.4.5. PMID 16382099. S2CID 10386627.
- ^ a b c d Wahl-Schott C, Baumann L, Cuny H, Eckert C, Griessmeier K, Biel M (October 2006). "Switching off calcium-dependent inactivation in L-type calcium channels by an autoinhibitory domain". Proceedings of the National Academy of Sciences of the United States of America. 103 (42): 15657–15662. Bibcode:2006PNAS..10315657W. doi:10.1073/pnas.0604621103. PMC 1622877. PMID 17028172.
- ^ a b c d Shaw RM, Colecraft HM (May 2013). "L-type calcium channel targeting and local signalling in cardiac myocytes". Cardiovascular Research. 98 (2): 177–186. doi:10.1093/cvr/cvt021. PMC 3633156. PMID 23417040.
Further reading
[edit]- Takahashi K, Hayashi S, Miyajima M, Omori M, Wang J, Kaihara K, et al. (May 2019). "L-type calcium channel modulates mechanosensitivity of the cardiomyocyte cell line H9c2". Cell Calcium. 79: 68–74. doi:10.1016/j.ceca.2019.02.008. PMID 30836292.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
External links
[edit]- "Voltage-Gated Calcium Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- L-Type+Calcium+Channel at the U.S. National Library of Medicine Medical Subject Headings (MeSH)