Voltage-gated calcium channels

Voltage-gated calcium channels mediate calcium influx in response to membrane depolarisation and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression. Their activity is essential to couple electrical signals in the cell surface to physiological events in cells. They are members of a gene superfamily of transmembrane ion channel proteins that includes voltage-gated potassium and sodium channels.

Calcium channels subunits
The calcium channels that have been characterised  biochemically are complex proteins composed of four or five distinct subunits, which are encoded by multiple genes (Figure 1). The 1 subunit of 190-250kDa is the largest subunit and it incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins. Like the  subunits of sodium channels, the 1 subunit of voltage-gated calcium channels is organised in four homologous domains (I-IV) with six transmembrane segments (S1-S6) in each. The S4 segment serves as the voltage sensor. The pore loop between transmembrane segments S5 and S6 in each domain determines ion conductance and selectivity, and changes of only three amino acids (aa) in the pore loops in domains I, III, and IV will concert a sodium channel to calcium selectivity. An intracellular  subunit and a transmembrane, disulphide-linked 2 subunit complex are components of most types of calcium channels.  A  subunit has also been found in skeletal muscle calcium channels and related subunits are expressed in heart and brain. Although these auxiliary subunits modulate the properties of the channel complex, the pharmacological and electrophysiological diversity of calcium channels arises primarily from the existence of multiple 1 subunits.

Calcium currents
Calcium currents recorded in different cell types have diverse physiological and pharmacological properties, and an alphabetical nomenclature has evolved for the distinct classes of calcium currents. L-type calcium currents require a strong depolarisation for activation, are long-lasting, and are blocked by the organic L-type calcium channel antagonists, including dihydropyridines, phenylalkylamines, and benzothiazepines. They are the main calcium currents recorded in muscle and endocrine cells, where they initiate contraction and secretion. N-type, P/Q-type, and R-type calcium currents also require strong depolarisation for activation. They are relatively unaffected by L-type calcium channel antagonist drugs but are blocked by specific polypeptide toxins from snail and spider venoms. They are expressed primarily  in  neurons, where they initiate neurotransmission at most fast synapses and also mediate calcium entry into cell bodies and dendrites. T-type calcium currents are activated by weak depolarisation and are transient. They are resistant to both organic antagonists and to the snake and spider toxins used to define the N- and IP/Q-type calcium currents. They are expressed in a wide variety of cell types, where they are involved in shaping the action potential and controlling patterns of repetitive firing.

Calcium channel genes
Mammalian 1 subunits are encoded by at least ten distinct genes. Historically, various names had been given to the corresponding gene products, giving rise to distinct and sometimes confusing nomenclatures. In 1994, a unified, but arbitrary nomenclature was adopted in which 1 subunits were referred to as 1S for the original skeletal muscle isoform and 1A through 1E for those discovered subsequently. In 2000, a rational nomenclature was adopted based on the well-defined potassium channel nomenclature. Calcium channels were named using the chemical symbol of the principal permeating ion (Ca) with the principal physiological regulator
(voltage) indicated as a subscript (Cav). The numerical identifier corresponds to the Cav channel 1 subunit gene subfamily (1 to 3 at present) and the order of discovery of the 1 subunit within that subfamily (1 through m). According to this nomenclature, the Cav1 subfamily (Cav1.1 to Cav1.4) includes channels containing 1S, 1C, 1D, and 1F, which mediate L-type Ca2+ currents (Table 1). The Cav2 subfamily (Cav2.1 to Cav2.3) includes channels containing 1A, 1B, and 1E, which mediate P/Q-type, N-type, and R-type Ca2+ currents, respectively (Table 1). The Cav3 subfamily (Cav3.1 to Cav3.3) includes channels containing 1G, 1H, and 1I, which mediate T-type Ca2+ currents.
To complete amino acid sequences of these 1 subunits are more than 70% identical within a family but less than 40% identical among families. These family relationships are illustrated for the more conserved transmembrane and pore domains in Figure 2. Division of calcium channels into these three families is phylogenetically ancient, as representatives of each are found in the C. elegans genome. Consequently, the genes for the different 1 subunits have become widely dispersed in the genome and even the most closely related members of the family are not clustered on single chromosomes.

Calcium channel molecular pharmacology
The pharmacology of the three families of calcium channels is quite distinct. The Cav1 channels are the molecular targets of the organic calcium channel blockers used widely in the therapy of cardiovascular diseases. These drugs are thought to act at three separate, but allosterically coupled, receptor sites (Table 1; reviewed in 8). Phenylalkylamines are intracellular pore blockers, which are thought to enter the pore from the cytoplasmic side of the channel and block it. Their receptor site is formed by amino acid residues in the S6 segments in domains III and IV, in close analogy to the local anaesthetic receptor site on sodium channels. Dihydropyridines can be channel activators or inhibitors, and therefore are thought to act allosterically to shift the channel toward the open or closed state, rather than by occluding the pore. Their receptor site includes amino acid residues in the S6 segments of domains III and IV and the S5 segment of domain III. The dihydropyridine receptor site is closely apposed to the phenylalkylamine receptor site and shares some common amino acid residues. Diltiazem and related benzothiazepines are thought to bind to a third receptor site; but the amino acid residues that are required for their binding overlap extensively with those required for phenylalkylamine binding.
The Cav2 family of calcium channels is relatively insensitive to dihydropyridine calcium channel blockers, but these calcium channels are specifically blocked with high affinity by peptide toxins from spiders and marine snails. The Cav2.1 channels are blocked specifically by -agatoxin IVA from funnel web spider venom. The Cav2.2 channels are blocked specifically by -conotoxin GVIA and related cone snail toxins. The Cav2.3 channels are blocked specifically by the synthetic peptide toxin SNX-482 derived from tarantula venom. These peptide toxins are potent blockers of synaptic transmission because of their specific effects on the Cav2 family of calcium channels. The Cav3 family of calcium channels is insensitive to both the dihydropyridines that block Cav1 channels and the spider and cone snail toxins that block the Cav2 channels, and there are no widely useful pharmacological agents that block T-type calcium currents.  The organic calcium channel blocker mibefradil is somewhat specific for T-type versus L-type calcium currents (three-to five-fold). The peptide kurtoxin inhibits the activation gating of Cav3.1 and Cav3.2 channels. Development of more specific and high affinity blockers of the Cav3 family of calcium channels would be useful for therapy and for more detailed analysis of the physiological roles of these channels.
This section of the compendium summaries the major molecular, physiological, and pharmacological properties for each of the ten calcium channels that have been functionally expressed.  Quantitative data are included for voltage-dependence of activation and inactivation, single-channel conductance, and binding of drugs and neurotoxins, focusing on those agents that are widely used and are diagnostic of channel identity and function.

Channel name    Cav1.1
Description    voltage-gated calcium channel 1 subunits
Other names    1s, skeletal muscle L-type Ca2+ channel, skeletal muscle dihydropyridine receptor
Molecular information    human: 1873aa, Q13698, L06234, chr.1q32, CACNA1S
rat: 1146aa (partial sequence), Q02485, L04684
mouse : 1351aa (partial sequence), L06234 (see Comments)
Associated subunits    2, , 
Functional assays    patch clamp (whole cell, single channel), calcium imaging, gating
charge movement, skeletal muscle contraction
Current    ICa,L
Conductance    1317pS (in 90110mM Ba2+)
Ion selectivity    Ca2+> Sr2+> Mg2+> Ba2+
Activation    Va= 8mV, a > 25ms at+10mV
Inactivation    Vh= 8mV; 40% current inactivation after 5s (5mV)
Activators    BayK8644, dihydropyridine agonists, FPL64176
Gating inhibitors    dihydropyridine antagonists (e.g. (+)- isradipine; IC50 = 13nMat at
90mV, 0.15nM at 65mV)
Blockers    selective: verapamil, devapamil (IC50 < 1M) and other phenyl-
alkylamines, (+)-cis-diltiazem (IC50 < 80M)
non selective : cadmium (IC50 < 0.5 mM)
Radioligands    (+)-3H-isradipine (Kd=0.20.7nM) and other dihydropyridines;
(-)-3H-devapamil, (Kd= 2.5nM), (+)-cis-3H-diltiazem (Kd =50nM)
Channel distribution    skeletal muscle transverse tubules (tetramers)
Physiological functions    excitation-contraction coupling and Ca2+ homeostasis in skeletal muscle
Mutations and pathophysiology    point mutations cause hypokalemic periodic paralysis and malignant hyperthermia susceptibility in humans and muscular dysgenesis in mice (mdg/mdg)
Pharmacological significance    not established
Comments    The gene for Cav1.1 was first isolated and characterised in rabbit (1873aa, PO7293, XO5921)

Channel name    Cav1.2
Description    voltage-gated calcium channel 1 subunits
Other names    1c, cardiac or smooth muscle L-type Ca2+ channel, cardiac or smooth muscle dihydropyridine receptor
Molecular information    human: 2221aa, Q13936 (cardiac), L04569 (cardiac) chr. 12p13.3, CACNA1C
rat: 2169aa, P22002 (cardiac) M59786
mouse : 2139aa, Q01815 (cardiac), L01776 (cardiac) (see Comments)
Associated subunits    2, , 
Functional assays    patch clamp (whole cell, single channel), calcium imaging, cardiac or
smooth muscle contraction hormone secretion
Current    ICa,L
Conductance    Ba2+ (25pS) > Sr2+ = Ca2+ (9pS)
Ion selectivity    Ca2+ > Sr2+> Ba2 >> Mg2+ from permeability ratios
Activation    Va= 4mV (in 15 mM Ba2+) to 17mV (in 2mM Ca2+); a = 1ms at +10mV
Inactivation    Vh = 50 to 60mV (in 2mM Ca2+),18 to 28mV (in 1015mM Ba2+);
fast = 150ms, slow = 1100ms (at Vmax in 15 mM Ba2+)
Activators    BayK8644, dihydropyridine agonists, FPL64176
Gating inhibitors    dihydropyridine antagonists (e.g. isradipine, IC50 = 7nM at 60mV; nimodipine, IC50  = 139nM at 80mV)
Blockers    selective: devapamil (IC50 = 50nM in 10mM Ba2+ at 60mV) and other
phenylalkylamines; diltiazem (IC50 = 33M in 10 mM Ba2+ at 60mV and 0.05Hz); non-selective: Cd2+
Radioligands    (+)-3H-isradipine (Kd < 0.1nM) and other dihydropyridines; () – 3H-devapamil, (Kd = 2.5nM), (+)-cis-3H-diltiazem ( Kd  = 50nM)
Channel distribution    cardiac muscle, smooth muscle (including blood vessels, intestine, lung, uterus); endocrine cells (including pancreatic -cells, pituitary); neurones
subcellular localisation: concentrated on granule-containing side of pancreatic -cells; on neurones preferentially located on proximal dendrites and cell bodies
Physiological functions    excitation-contraction coupling in cardiac or smooth muscle, action potential propagation in sonoatrial and atrioventricular node, synaptic plasticity, hormone secretion
Mutations and pathophysiology    required for normal embryonic development (mouse, zebrafish)
Pharmacological significance    mediates cardiovascular effects of clinically used Ca2+ antagonists
Comments    Tissue-specific splice variants exist; in addition to cardiac channels, smooth muscle (2169aa) and brain (2140-2144aa) channels have been cloned. The gene for Cav1.2 was first isolated and characterised in rabbit (2171aa, P15381, X15539)

Foot Pad

Channel name    Cav1.3
Description    voltage-gated calcium channel 1 subunit
Other names    1d ‘neuroendrocrine’ L-type Ca2+ channel
Molecular information    human: 2161aa (brain), Q01668, M76558. chr. 3p14.3, CACNA1D
rat: 1646aa (brain), M57682 (see Comments)
Associated subunits    most likely at least 2, , and  subunits
Functional assays    patch clamp (whole cell, single channel), calcium imaging
Current    ICa,L
Conductance    not established
Ion selectivity    not established
Activation    Va= 18mV (in 15 mM Ba2+) to 20mV (in 2mM Ca2+); a < 1ms at +10mV
Inactivation    Vh = 27 to 57mV fast = 190ms, slow = 1700ms (at Vmax)
Activators    BayK8644
Gating inhibitors    dihydropyridine antagonists (e.g. isradipine, IC50 = 30nM at 50mV,
300nM at 90mV; nimodipine, IC50  = 3M at 80mV)
Blockers    non selective: Cd2+
Radioligands    (+)-3H-isradipine (Kd < 0.5nM)
Channel distribution    sensory cells (photoreceptors, cochlear hair cells), endocrine cells (including pancreatic -cells, pituitary, adrenal chromaffin cells, pinealocytes), low density in heart (atrial muscle, sinoatrial and atrioventricular node) and vascular smooth muscle; neurones
subcellular localisation: on neurones preferentially located on proximal
dendrites and cell bodies
Physiological functions    neurotransmitter release in sensory cells, control of cardiac rhythm and atrioventricular node conductance at rest, synaptic plasticity, hormone
secretion
Mutations and pathophysiology    deafness, sinoatrial and atrioventricular node dysfunction, insulin secretion defect in knockout mice
Pharmacological significance    hypothetical drug target for modulators of heart rate and insulin secretion
Comments    Tissue-specific splice variants exist; in addition to brain, pancreatic -cell
(2181aa in human, 2203aa in rat) and cochlear channels have been cloned

Channel name    Cav1.4
Description    voltage-gated calcium channel 1 subunit
Other names    1f
Molecular information    human: 1966aa, O60840, AJ224874, chr. Xp11.23, CACNA1F
rat: 1981aa, AF365975
mouse: 1985aa, AF192497
Associated subunits    not established
Functional assays    patch clamp (whole cell, single channel), calcium imaging
Current    functional expression has not been reported
Conductance    not established
Ion selectivity    not established
Activation    not established
Inactivation    not established
Activators    not established, expected to be sensitive to dihydropyridine agonists
(e.g. BAYK8644)
Gating inhibitors    not established, expected to be sensitive to dihydropyridine antagonists
Blockers    not established
Radioligands    none
Channel distribution    retinal photoreceptors and ganglion cells
Physiological functions    neurotransmitter release in retinal cells
Mutations and pathophysiology    mutations cause X-linked congenital stationary night blindness type 2
Pharmacological significance    not established
Comments

Channel name    Cav2.1
Description    voltage-gated calcium channel 1 subunit
Other names    1A, P-type, Q-type, rbA-I (in rat); BI-1, BI-2 (in rabbit)
Molecular information    human: 2510aa, AF004883, 2662aa, AF004884, chr. 19p13, CACNA1A
rat: 2212aa, M64373
mouse: 2165aa, NM007578, NP031604  (see Comments)

Associated subunits    2, ,  possibly 
Functional assays    voltage clamp, patch clamp, calcium imaging, neurotransmitter release
Current    ICa, P, ICa, Q
Conductance    9, 14, 19pS (T-type, cerebellar Purkinje neurones); 16-17pS (for 1A/2/ in Xenopus oocytes)
Ion selectivity    Ba2 > Ca2+
Activation    Va= 5mV for native P-type, Va  = 11 mV for native Q-type (with 5mM
Ba2+ charge carrier)
Va= 4.1mV for rat 1A-a/2/4
Va= +2.1mV for rat 1A-b/2/4 (with 5 mM Ba2+ charge carrier)
Va= +9.5mV; a = 2.2ms at + 10mV for human 1A-1/2/1b in HEK 293
cells (with 15mM Ba2+ charge carrier)
Inactivation    Vh = 17.2mV for 1A-a/2/4, Vh = 1.6mV for 1A-b/2/4 (with 5mM Ba2+  charge carrier); Vh = 17mV, h = 690ms at + 10mV human 1A-1/2/1b in HEK 293 cells (with 15 mM Ba2+ charge carrier); h > 1s at 0mV native P-type (with 5 mM Ba2+ charge carrier)  (see Comments)
Activators    none
Gating inhibitors    -agatoxin IVA (P-type Kd =13nM ; Q-type Kd  100200nM ,
-agatoxin IVB
Blockers    -conotoxin MVIIC (see Comments)
Radioligands    125I --conotoxin MVIIC
Channel distribution    neurones (presynaptic terminals, dendrites, some cell bodies), heart, pancreas, pituitary
Physiological functions    neurotransmitter release in central neurones and neuromuscular junction; excitation-secretion coupling in pancreatic  cells
Mutations and pathophysiology    point mutations in IS4, IVS6 and IIS5-S6 linker cause familiar hemiplegic migraine; point mutations in IIIS1 and S2 cause episodic ataxia type -2; a polyglutamine expansion in the carboxyl region causes spinocerebellar ataxia type-6; and mutation of IS5-S6 causes episodic and progressive ataxia
Pharmacological significance    peptide toxins that selectively inhibit Cav2.1 channel blocks a significant
portion of neurotransmission in the mammalian CNS; block of Cav2.1 channels inhibits the late phase formalin response and inflammatory pain but has no significant effect on mechanical allodynia of thermal hyperalgesia; mice lacking a functional Cav2.1 gene exhibit cerebellar atrophy, severe muscle spasms and ataxia and usually die by three to four weeks postnatal
Comments    The gene for Cav2.1 was also isolated and characterised in rabbit (2273aa, X57476). Rates of 1A inactivation and Vh are differentially affected by co-expression with 1b, 2a, 3 or 4 subunits, as well as by alternative splicing of the 1A subunit.
Whole cell currents with P-type kinetics appear to be conducted by the
1A-b splice variant co-expressed with any of the  subunits, or by the 1A-a
splice variant co-expressed with the 2a subunit. Whole cell currents with Q-type kinetics appear to be encoded by 1A-a co-expressed with any of the 1b, 3 or 4 subunits.
Whole cell currents with Q-type pharmacology appear to be encoded by
1A splice variants containing Asp Pro residues in the domain IV S3-S4 linker, while whole cell currents with P-type pharmacology appear to be encoded by 1A splice variants missing Asp Pro residues in IV S3-S4 linker.

Channel name    Cav2.2
Description    voltage-gated calcium channel 1 subunit
Other names    N-type, 1B; rbB-I, rbB-II (in rat), BIII (in rabbit)
Molecular information    human: 2339aa, M94172, 2237aa, M94173, chr. 9q34, CACNA1B
rat: 2336aa, M92905
mouse: 2329aa, NM007579, NP031605
Associated subunits    2/1, 3, 4 possibly 
Functional assays    voltage clamp, patch clamp, calcium imaging, neurotransmitter release, Ca uptake into synaptosomes
Current    ICa,N
Conductance    20pS (bullfrog sympathetic neurones); 14.3pS (rabbit BIII cDNA in skeletal muscle myotubes)
Ion selectivity    Ba2+ > Ca2+
Activation    Va= +7.8mV, a = 3ms at + 10mV (human 1B/2/1-3 in HEK 293 cells,
15mM Ba2+  charge carrier); Va = +9.7mV, a = 2.8ms at + 20mV (rat 1B-II/
1b, in Xenopus oocytes, 40mM Ba2+ charge carrier)
Inactivation    Vh = 61mV, h  200ms at +10mV (human 1B/2/1-3 in HEK 293 cells, 15mM Ba2+  charge carrier); Vh = 67.5mV; h = 112ms at +20mV (rat 1B- II /1b in Xenopus oocytes, 40 mM Ba2+)
Activators    none
Gating inhibitors     none
Blockers    -conotoxin GVIA (1-2M, irreversible block), -conotoxin MVIIA (SNX-111, ziconotide), -conotoxin MVIIC
Radioligands    125I --conotoxin GVIA (Kd = 55pM, human 1B/2/1-3 in HEK 293 cells)
Channel distribution    neurones (presynaptic terminals, dendrites, cell bodies)
Physiological functions    peptide toxins that selectively inhibit N-type channels block a significant fraction of neurotransmission release in the mammalian peripheral and central nervous systems
Mutations and pathophysiology    differing reports exist: mice lacking a functional Cav2.2 gene exhibit a normal life span and no detectable behavioural modifications compared to wild type, but possess an increase in basal mean atrial pressure and other functional alterations to the sympathetic nervous system, approx. 1/3 of mice lacking a functional Cav2.2 gene did not survive to weaning but surviving animals were normal except for a decrease in anxiety-related behaviour and a suppression of inflammatory and neuropathic pain responses; no point mutations in the native Cav2.2 gene have been reported to date
Pharmacological significance    in rats, intrathecal administration of -conotoxin GVIA or -conotoxin MVIIA shows strong effects on inflammatory pain, post-surgical pain, thermal hyperalgesia and mechanical allodynia; in humans, intrathecal administration of SNX-111 (ziconotide, synthetic -conotoxin MVIIA) to patients unresponsive to intrathecal opiates significantly reduced pain scores and in a number of specific instances resulted in relief after many years of continuous pain
Comments    In case studies, ziconotide has been examined for usefulness in the management of intractable spasticity following spinal cord injury in patients unresponsive to baclofen and morphine. Side effects of intrathecal administration of ziconotide include nystagmus, sedation, confusion, auditory and visual hallucinations, severe agitation and unruly behaviour. Intravenous administration of ziconotide to humans results in significant orthostatic hypotension

Channel name    Cav2.3
Description    voltage-gated calcium channel 1 subunit
Other names    R-type, 1E; rbE-II (in rat); BII-1, BII-2 (in rabbit)
Molecular information    human: 2251aa, L29384, 2270aa, L29385, chr. 1q25-q31, CACNA1E
rat: 2222aa, Genbank L15453);
mouse: 2272aa, Q61290
Associated subunits    2/, possibly 
Functional assays    voltage clamp, patch clamp, calcium imaging, neurotransmitter relase
Current    ICa,R
Conductance    not established
Ion selectivity    Ba2+  Ca2+ (rat); Ba2+ > Ca2+ (human)
Activation    Va = +3.5mV, a = 1.3ms at + 0mV (human 1E/2/1-3, 15mM Ba2+ charge carrier in HEK 293 cells)
Va =29.1mV; a = 2.1ms at 10mV (rat 1E/2/1b, 4mM Ba2+ charge carrier in Xenopus oocytes)
Inactivation    Vh = 71mV; h = 74ms at 0mV (human 1E/2/1-3 15mM Ba2+ charge carrier in HEK 293 cells);
Vh = 78.1mV, h = 100ms at 10mV (rat 1E/2/1b, 4mM Ba2+ charge carrier in Xenopus oocytes)
Activators    none
Gating inhibitors    none
Blockers    SNX-482, Ni2+ (IC50 = 27M), Cd2+ (IC50 = 0.8M)
Radioligands    none
Channel distribution    neurones (cell bodies, dendrites, some presynaptic terminals), heart, testes, pituitary
Physiological functions    neurotransmitter release, repetitive firing
Mutations and pathophysiology    no point mutations in the native Cav2.3 gene have been reported; mice deficient for the Cav2.3 gene retain a substantial cerebellar R-type current suggesting that R-type currents actually reflect a heterogeneous mixture of channels; homozygous Cav2.3 null mice survive to adulthood, reproduce and are apparently behaviourally normal; mutant mice exhibit an increased resistance to formalin-induced pain suggesting an involvement of the Cav2.3 calcium channel in transmitting and/or the development of somatic inflammatory pain
Pharmacological significance    see Comments
Comments    Cav2.3 has been variously reported to encode a novel type of calcium channel with properties shared between both low and high threshold calcium channels, or a type of high threshold channel resistant to DHPs, -agatoxin-IVA and -conotoxin-GVIA and called R-type (for ‘residual’).
The tarantula toxin, SNX-482, blocks exogenously expressed Cav2.3 currents but is only partially effective on native cerebellar R-type currents suggesting that Cav2.3 does not always conduct a significant portion of the R-type current as originally defined.

Channel name    Cav3.1
Description    voltage-gated calcium channel 1 subunit
Other names    T-type, 1G, CavT.1
Molecular information    human: 2171aa, O43497, NP_061496, chr. 17q22, CACNA1G
rat: 2254aa, O54898, AAC67372,
mouse: 2288aa, Q9WUB8, NP_033913 (see Comments)
Associated subunits    no biochemical evidence, small changes induced by 21 and 22
Functional assays    voltage clamp, calcium imaging
Current    ICa,T
Conductance    7.5pS
Ion selectivity    Sr2+ > Ba2+ = Ca2+
Activation    Va = 46mV; h = 1ms at 10mV
Inactivation    Vh = 73mV; h = 11ms at 10mV
Activators    not established
Gating inhibitors    kurtoxin, IC50 = 15nM
Blockers    no sub-type specific blocker
selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil, U92032, and pimozide
non selective: nickel (IC50 = 250M), amiloride
Radioligands    none
Channel distribution    brain, especially soma and dendrites of neurones in olfactory bulb, amygdala, cerebral cortex, hippocampus, thalamus, hypothalamus, cerebellum, brain stem (human RNA blots, rat in situ hybridisation, and immunocytechemistry); ovary, placenta, heart (especially sinoatrial node; mouse in situ hybridisation)
Physiological functions    thalamic oscillations, possibly cardiac pacemaking
Mutations and pathophysiology    not established
Pharmacological significance    thalamocortical dysrhythmias
Comments    Splice variants that differ in their voltage dependence have been cloned

Channel name    Cav3.2
Description    voltage-gated calcium channel 1 subunit
Other names    T-type, 1H, CavT.2
Molecular information    human : 2353aa, O95180, AAC67239, chr.16p13.3, CACNA1H
rat: 2359aa, Q9EQ60, AAG35187
mouse: 2365aa, NP_67390
Associated subunits    not established
Functional assay    voltage clamp, calcium imaging
Current    ICa,T
Conductance    9pS
Ion selectivity    Ba2+ = Ca2+
Activation    Va = 46mV; a = 2ms at 10mV
Inactivation    Vh = 72mV; h = 16ms at 10mV
Activators    none
Gating inhibitors    kurtoxin
Blockers    Cav3.2 is more sensitive than Cav3.1 to block by phenytoin, and possibly amiloride
selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil, U92032, pimozide, amiloride, nickel (IC50 = 12M)
non selective : nimodipine, anaesthetics
Radioligands    none
Channel distribution    kidney (human northern), rat smooth muscle (RT-PCR), liver (human northern), adrenal cortex (rat, bovine, in situ hybridisation and RT-PCR), brain (especially in olfactory bulb, striatum, cerebral cortex, hippocampus, reticular thalamic nucleus; rat in situ hybridisation), and heart (especially sinoatrial node; mouse in situ hybridisation)
Physiological functions    smooth muscle contraction, smooth muscle proliferation, aldosterone secretion, cortisol secretion
Mutations and pathophysiology    not established
Pharmacological significance    potential drug target in hypertension and angina pectoris

Channel name    Cav3.3
Description    voltage-gated calcium channel 1 subunit
Other names    T-type, 1I
Molecular information    human : 2251aa, Q9UNE6, XP_001125, chr. 22q12.3-13.2, CACNA1I
rat: 1835aa, Q970Y8, AAD17796
mouse : not cloned
Associated subunits    no biochemical evidence, small changes induced by 2
Functional assays    voltage clamp, calcium imaging
Current    ICa,T
Conductance    11pS
Ion selectivity    Ba2+ = Ca2+
Activation    Va = 44mV; a = 7ms at 10mV
Inactivation    Vh = 72mV; h = 69ms at 10mV
Activators    not established
Blockers    no sub-type specific blocker
selective for Cav3.x relative to Cav1.x and Cav2.x: mibefradil, U92032, and pimozide
non-selective : nickel (IC50 = 216M)
Radioligands    none
Channel distribution    brain, especially olfactory bulb, striatum, cerebral cortex, hippocampus, reticular nucleus, lateral habenula, cerebellum (rat in situ hybridisation, human northern)
Physiological functions    thalamic oscillations
Mutations and pathophysiology    not established
Pharmacological significance    thalamocortical dysrhythmias
Comments    Splice variants have been reported

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Posted on มกราคม 15, 2013, in บทความ. Bookmark the permalink. ใส่ความเห็น.

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