Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Calcium channels

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Calcium channels

Calcium channels

Calcium is a critical cellular cation that mediates both physiological andpathological events. Ca2+ physiologic roles include primarily mediation ofstimulus-response coupling and maintenance of cellular integrity. Ca2+ entry, efflux,mobilization, and storage are controlled by wide range of proteins: voltage-gated andreceptor-operated Ca2+ channels, Na+:Ca2+ exchangers, Ca2+ pumps and Ca2+ storage siteswithin mitochondria and sarcoplasmic reticulum [1].

Voltage-gated calcium channels mediate calcium influx in response to membranedepolarization and regulate intracellular processes, such as contraction, secretion,neurotransmission, and gene expression. Their activity is essential to couple electricalsignals on the cell surface to physiological events in the cells. Calcium channels arecomplex proteins composed of four or five distinct subunits. The conduction pore, voltagesensor, and gating apparatus are incorporated in the largest alpha 1 subunit. Differenttypes of calcium currents are mediated by channels containing different alpha 1 subunits.L-type calcium currents require a strong depolarization and are main calcium currentsfound in muscle and endocrine cells, where they initiate contraction and secretion.L-type currents are mediated by channels containing Calcium channel voltage-dependent Ltype alpha 1S subunit ( CACNA1S ), Calcium channel, voltage-dependent L type alpha1D subunit ( CACNA1D ), L-type Ca(II) channel, alpha 1C subunit, Calciumchannel voltage-dependent L type alpha 1F subunit ( CACNA1F ). N-type, P/Q-type,and R-type calcium currents also require strong depolarization for activation and aremediated by N-type Ca(II) channel alpha1B, P/Q-type calcium channel alpha-1Asubunit and Calcium channel voltage-dependent L type alpha 1F subunit (CACNA1E ), respectively. These types of currents are expressed primarily inneurons, where they initiate neurotransmission at most fast synapses and mediate calciumentry into cell bodies and dendrites. T-type calcium currents are activated by weakdepolarization and are served by Calcium channel voltage-dependent L type alpha 1Hsubunit ( CACNA1H ), Calcium channel voltage-dependent L type alpha 1I subunit (CACNA1I ) and Calcium channel voltage-dependent L type alpha 1G subunit (CACNA1G ) containing channels [2].

Ca2+ channel activity could be modulated by Cysteine rich protein ( Csp ) -secretory vesicle proteins,-which interactws with N-type Ca(II) channel alpha1Band P/Q-type calcium channel alpha-1A subunits [3].

Transient Receptor Potential Cation Channels (TRP) contribute to changes in thecytosolic calcium concentration either by acting as calcium entry pathways in the plasmamembrane, or via changes in membrane polarization, modulating the driving force forcalcium entry mediated by alternative pathways. Mammalian TRP channels can be subdividedinto six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin),TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels arepermeable to Ca2+ with the exceptions of TRPM4 and TRPM5, which are onlypermeable to monovalent cations. Most Ca2+-permeable TRP channels are only poorlyselective for Ca2+, with permeability ratio relative to Na+ ranging from 0.3 to 10 [4].

TRPC members are considered as channels activated upon stimulation of receptors thatactivate phospholipase C. TRPC channels play role in vasomotor function ( TRPC4,TRPC6 ), growth cone morphology, and guidance ( TRPC5 ) [4]..

TRPV1 - TRPV4 are all heat-activated channels that are nonselective forcations. TRPV1 for instance, is involved in pain sensation, spicy taste perceptionand noxious temperature detection [4].

TRPM channels exhibit highly variable permeability to Ca2+, and gating mechanisms ofthe TRPM subfamily members are equally varied: TRPM2 is activated by intracellularADP-ribose (ADPR), hydrogenperoxide, and heat, whereas reported activation mechanisms forTRPM3 include cell swelling and sphingosine; TRPM4 and TRPM5 is activatedupon a rise in intracellular Ca2+ and are further strongly activated by heating.TRPM8 is activated by cooling and by cooling agents [4].

Nicotinic acetylcholine receptors ( nAChR ) are ligand-gated cation channelswidely distributed in both the nervous system and non-neuronal tissues. Their opening iscontrolled by the endogenous neurotransmitter acetylcholine or exogenous ligands, such asnicotine. nAChR consist of homopentameric or heteropentameric subtypes. In theCNS, acetylcholine-mediated innervation via nAChR regulates processes such astransmitter release, cell excitability, and neuronal integration. nAChR areinvolved in pathological conditions, such as Alzheimer's disease, Parkinson's disease,some forms of epilepsy, depression, autism, and schizophrenia. They are also targets oftobacco-smoking effects and addiction [5], [6].

N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionicacid (AMPA) receptors are ionotropic glutamate receptors. Native receptors of thesefamilies are likely tetromeric assemblies comprising more than one type of subunit.NMDA receptor is unique amongst ligand-gated ion channels in its requirement fortwo obligatory co-agonists, binding at the glycine and glutamate binding sites. Highpermeability to calcium ions, confers NMDA receptors' central role in both,synaptic plasticity under physiological conditions and neuronal death under excitotoxicpathological conditions [7], [8]. NMDA receptors areabundant in postsynaptic membrane, where they are anchored in so-called postsynapticdensity (PSD) by Discs, large homolog 4 ( PSD-95 ). PSD-95 functions as ascaffold to assemble a specific set of signaling proteins around the NMDA receptor [9].

AMPA receptors also mediate fast synaptic transmission at excitatory synapsesin CNS and are crucial during neuronal development, synaptic plasticity, and structuralremodeling [10].