L-type calcium channel

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Calcium channel, voltage-dependent
L-type calcium channel 3JBR.png
Crystallographic structure of the L-type calcium channel complex (subunits α1S, α2, δ, β, and γ).
Identifiers
SymbolCalcium channel, voltage-dependent
Immunohistochemical analysis of L-type calcium channel Cav1.3 (CACNA1D) in human adrenal cortex. Marked immunoreactivity was detected in the zona glomerulosa. In the figure: ZG = zona glomerulosa, ZF = zona fasciculata, AC = adrenal capsule. Immunohistochemistry was performed according to published methods. L-type D-subtype CaV1.3 calcium channel CACNA1D in human adrenal zona glomerulosa.jpg
Immunohistochemical analysis of L-type calcium channel Cav1.3 (CACNA1D) in human adrenal cortex. Marked immunoreactivity was detected in the zona glomerulosa. In the figure: ZG = zona glomerulosa, ZF = zona fasciculata, AC = adrenal capsule. Immunohistochemistry was performed according to published methods.
An L-type calcium channel with its subunits labeled along with some drugs known to inhibit the channel. General L-type calcium channel.jpg
An L-type calcium channel with its subunits labeled along with some drugs known to inhibit the channel.

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.

Contents

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

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 would open to 1,4-dihydropyridine (DHPs). [6] Using DHPs, they 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: α1S (Skeletal Muscle), α1C (Cardiac), α1 D (found in the brain), and α1F (found in the retina). [6] In 2000, after more research was done on α1 subunits in voltage-gated calcium channels, a new nomenclature was used that called L-type calcium channels CaV1 with its subunits being called CaV1.1, Cav1.2, CaV1.3, and CaV1.4. [3] Research on the CaV1 subunits continues to reveal more about their structure, function, and pharmaceutical applications. [7]

Structure

L-type Calcium Channels contain 5 different subunits, the α1(170–240 kDa), α2(150kDa), δ(17-25 kDa), β(50-78 kDa), and γ(32 kDa) subunits. [8] The α2, δ, and β subunits are non-covalently bonded to the α1 subunit and modulate ion trafficking and biophysical properties of the α1 subunit. The α2 and δ subunits are in the extracellular space while the β and γ subunits are located in the cytosolic space. [8]

The α1 subunit is a heterotetramer that has four transmembrane regions, known as Domains I-IV, that cross the plasma six times as α-helices, being called S0-S6 (S0 and S1 together cross the membrane once). [3] The α1 subunit as a whole contains the voltage sensing domain, the conduction pore, and gating apparatus. [9] Like most voltage-gated ion channels, the α-subunit is composed of 4 subunits. Each subunit is formed by 6 alpha-helical, transmembrane domains that cross the membrane (numbered S1-S6). The S1-S4 subunits make up the voltage sensor, while S5-S6 subunits make up the selectivity filter. [10] To sense the cell's voltage, the S1-S3 helices contain many negatively charged amino acids while S4 helices contain mostly positively charged amino acids with a P-loop connecting the S4 to S5 helices. After the S1-6 domains, there are six C domains that consist of two EF-hand motifs (C1-2 and C3-4) and a Pre-IQ domain (C5) and IQ domain (C6). There are also two EF-hand motifs on the N-terminus. Both the N and C terminus are in the cytosolic space with the C-terminus being much longer than the N-terminus. [11]

The β subunit is known to have four isoforms (β1-β4) to regulate the channel's functions and is connected to α1 through the α1 I and II linker in the cytosol at the β α1-binding pocket (ABP). [7] [12] Each isoform contains a src homology 3 domain (SH3) and a guanylate-kinase like domain (GK) that are separated by a HOOK domain, and three unstructured regions. [12]

The α2 and δ subunits are connected together by disulfide bonds (sometimes known as the α2δ subunit) and interact with α1. [7] they have four known isoforms called α2δ-1 to α2δ-2 and contain a von Willebrand A (VWA) domain and a Cache domain. The α2 region is in the extracellular space while the δ region is in the cell membrane and have been seen to be anchored with a glycosylphosphatidylinositol (GPI) anchor. [12]

The γ subunit has eight isoforms (γ1-γ8) and is connected to the α1 subunit and has only been found in muscle cells in the CaV1.1 and CaV1.2 channels. [12] Not much is known about the γ subunit, but it has been linked to interactions in hydrophobic forces. [3]

Mechanism

Opening of the pore in L-type calcium channels takes place in the α1 subunit. When the membrane depolarizes, the S4 helix moves through the S4 and S5 linkers to the cytoplasmic ends of the S5 and S6 helices. This opens the activation gate which is formed by the inner side of the S6 helices in the α1 subunit. [11]

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

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 α-helix on the C-terminal called the DCRD and a negatively charged helix right after the IQ motif (CaM interaction site) called the PCRD. The two helices can form a structure that bind competitively with CaM to reduce the open-state probability and lower calcium-dependent inhibition (CDI). [7]

Alternative splicing is also seen on the β subunits to create different isoforms to give channels different properties due to palmitoylation [6] and RNA editing. [7] Other forms of modulation on the β subunit include increasing or decreasing of the subunit's expression. This is due to the fact that β subunits increase the open-probability of the channel, activity in the plasma membrane, and antagonize the ubiquitination of the channel. [6]

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 β-adrenergic receptor is stimulated to increase activation of the channels. [6]

Alpha subunit of a generic voltage-gated ion channel Alphasubunit sodium channel.png
Alpha subunit of a generic voltage-gated ion channel

Genes

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

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Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

<span class="mw-page-title-main">Cardiac action potential</span> Biological process in the heart

The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

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Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

Ca<sub>v</sub>1.2 Protein-coding gene in humans

Calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that in humans is encoded by the CACNA1C gene. Cav1.2 is a subunit of L-type voltage-dependent calcium channel.

<span class="mw-page-title-main">SK channel</span> Protein subfamily of calcium-activated potassium channels

SK channels are a subfamily of calcium-activated potassium channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.

<span class="mw-page-title-main">N-type calcium channel</span> Protein family

N-type calcium channels also called Cav2.2 channels are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells. The calcium N-channel consists of several subunits: the primary subunit α1B and the auxiliary subunits α2δ and β. The α1B subunit forms the pore through which the calcium enters and helps to determine most of the channel's properties. These channels play an important role in the neurotransmission during development. In the adult nervous system, N-type calcium channels are critically involved in the release of neurotransmitters, and in pain pathways. N-type calcium channels are the target of ziconotide, the drug prescribed to relieve intractable cancer pain. There are many known N-type calcium channel blockers that function to inhibit channel activity, although the most notable blockers are ω-conotoxins.

Ca<sub>v</sub>1.1 Mammalian protein found in Homo sapiens

Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene. It is also known as CACNL1A3 and the dihydropyridine receptor.

<span class="mw-page-title-main">CACNB1</span> Protein-coding gene in the species Homo sapiens

Voltage-dependent L-type calcium channel subunit beta-1 is a protein that in humans is encoded by the CACNB1 gene.

Ca<sub>v</sub>1.3 Protein-coding gene in the species Homo sapiens

Calcium channel, voltage-dependent, L type, alpha 1D subunit is a protein that in humans is encoded by the CACNA1D gene. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

<span class="mw-page-title-main">Calcium channel, voltage-dependent, T type, alpha 1H subunit</span> Protein-coding gene in the species Homo sapiens

Calcium channel, voltage-dependent, T type, alpha 1H subunit, also known as CACNA1H, is a protein which in humans is encoded by the CACNA1H gene.

<span class="mw-page-title-main">Gating (electrophysiology)</span>

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

The ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family includes Ryanodine receptors and Inositol trisphosphate receptors. Members of this family are large proteins, some exceeding 5000 amino acyl residues in length. This family belongs to the Voltage-gated ion channel (VIC) superfamily. Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP3 receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca2+ into the cytoplasm upon activation (opening) of the channel. They are redox sensors, possibly providing a partial explanation for how they control cytoplasmic Ca2+. Ry receptors have been identified in heart mitochondria where they provide the main pathway for Ca2+ entry. Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1;TC# 1.A.3.1.2) by NADPH oxidase 4.

References

  1. 1 2 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.
  2. ↑ 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.
  3. 1 2 3 4 5 6 7 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.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 3 4 5 6 7 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.
  7. 1 2 3 4 5 6 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.
  8. 1 2 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.
  9. ↑ "Voltage-gated calcium channels | Introduction | BPS/IUPHAR Guide to PHARMACOLOGY". www.guidetopharmacology.org. Retrieved 2019-11-28.
  10. ↑ 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.
  11. 1 2 3 4 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.
  12. 1 2 3 4 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

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