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Sodium channels and transporters: inward current


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Sodium channels and transporters: inward current

Sodium channels and transporters: inward current

Inward sodium currents are provided by wide range of sodium channels and transporters.Based on the mechanism of opening, sodium channels are classified into ligand-gated andvoltage-gated.

Voltage-gated sodium channels are heteromeric complexes consisting of a large centralpore-forming glycosylated alpha subunit and two auxiliary beta subunits. Beta subunitsregulate channel gating. There are nine known alpha subunit groups [1].Voltage-gated sodium channels belong to a primary class of ion channels responsible fordriving neuronal excitability in both the central and peripheral nervous system.Generally, inward sodium current is associated with rising phase of action potential.Sodium channel voltage-gated, type I alpha subunit ( Na(v) I alpha ), Sodiumchannel voltage-gated type II alpha subunit ( SCN2A ), Sodium channelvoltage-gated type III alpha subunit ( SCN3A ) and Sodium channel voltage gatedtype VIII alpha subunit ( Nav1.6 ), are expressed at high levels in the centralnervous system (CNS).

Two channel isoforms are abundant in muscles. In adult skeletal muscle Sodium channelvoltage-gated type IV alpha subunit ( SCN4A(SkM1) ) is expressed. Sodium channelvoltage-gated type V alpha subunit ( Tetrodotoxin-resistant Na(I) ) was detectedin embryonic and denervated skeletal muscle and heart muscle. Three muscle diseases, longQT syndrome type 3 (LQT3), Brugada's syndrome, and idiopathic ventricular fibrillation(IVF) are associated with the second type of isoforms [2]. Three isoforms,Sodium channel voltage-gated type IX alpha subunit ( SCN9A ), Sodium channelvoltage-gated type X alpha subunit ( SCN10A ) and Sodium channel voltage-gatedtype XI alpha subunit ( Nav1.9 ) are expressed primarily in the peripheral nervoussystem [3]. The SCN9A channel is crucial for generating excitabilitythrough all-or-none action potentials. This type of channel is present mainly inendocrine cells and in cells crucial for nociception [1].

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: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP(polycystin), TRPML (mucolipin), and TRPA (ankyrin). TRP channels are permeable to Ca2+.However, TRPM4 and TRPM5, as an exception, are permeable only tomonovalent cations. Most Ca2+-permeable TRP channels are only poorly selective for Ca2+,with permeability ratio relative to Na+ in the range of 0.3 to 10 [4].

TRPC channels are activated subsequent to stimulation of receptors that activatephospholipase C. TRPC channels play role in vasomotor function ( TRPC4,TRPC6 ), growth cone morphology and guidance ( TRPC5 ).

TRPV channels are all heat-activated channels that are nonselective forcations. Capsaicin receptor for example is involved in pain sensation, spicy tasteperception and noxious temperature detection.

TRPM channels exhibit highly variable permeability to Ca2+, the gating mechanisms ofthe TRPM subfamily members are equally varied. Notably TRPM2 is activated byintracellular ADP-ribose (ADPR), hydrogen peroxide, and heat, whereas reported activationmechanisms for TRPM3 include cell swelling and sphingosine. At the same time,TRPM4 and TRPM5 gate upon a rise in intracellular Ca2+ and are furtherstrongly activated by heating. TRPM8 is activated upon cooling and by coolingagents [4].

Amiloride-sensitive cation channels 1-3 ( BNaC1(ASIC2), BnaC2(ASIC1a),ACCN3(ASIC3) ) are activated by protons and are therefore classified asAcid-sensing ion channels (ASICs). Typical ASIC current displays a Na+/K+ selectivityratio d10, ASICs show some permeability to Ca2+. ASIC channels are thought to be involvedin pain perception, especially following tissue acidosis [5].

Purinergic receptor P2X (P2X) family of ligand-gated ion channel receptors areactivated by extracellular ATP and are permeable to Na+, K+ and Ca2+. P2X receptorsopening causes cell depolarization by cationic influx. P2X receptors play role in smoothmuscle contraction, neuronal excitation, inflammation and cell death [6],[7].

Unlike most voltage-gated channels, Hyperpolarization-activated cation channels of theHCN gene family, such as Hyperpolarization activated cyclic nucleotide-gated potassiumchannel 1 ( HCN1 ), are activated by hyperpolarizing voltage steps to negativepotentials to -60 mV, which is near the resting potentials of most cells. The HCNchannels are regulated by cyclic nucleotides and have unusual ion selectivity in thatthey conduct both Na+ and K+ ions but exclude Li+. The ratio of the K+ to Na+permeability of the channel ranges from 3:1 to 5:1, yielding values for the reversalpotential of -25 to -40 mV. As a result, activation of the channel at typical restingpotentials results in a net inward current carried largely by Na+. The latter depolarizesthe membrane toward threshold for firing an action potential. HCN channels contribute tospontaneous rhythmic activity in both heart and brain and Ih-current provided by thesechannels is often referred to as the pacemaker current. It also plays important role insensory transduction of visual, taste and olfactory stimuli [8], [9].

Solute carrier family 5 member 1 ( SLC5A1 ), Solute carrier family 5 member 5 (SLC5A5 ) and Solute carrier family 5 member 4 ( SGLT3 ) all correspond tosodium/glucose cotransporter gene family (SLC5). SLC5A1 is expressed primarily inthe brush border membrane of mature enterocytes in the small intestine where it absorbsdietary D-glucose and D-galactose from the gut lumen. It transports two Na+ ionssimultaneously with one sugar molecule. SLC5A5 is a Na+/iodide co-transporterfound principally in the thyroid gland where it is responsible for the accumulation ofiodide necessary for thyroid hormones. Human SGLT3 is not a Na+/sugar transporter,but rather a glucose-gated ion channel expressed in muscle and neurons [10],[11].

Epithelial sodium channels ( ENaC ) are located in the apical membrane ofpolarized epithelial cells where they mediate Na+ transport across tight epithelia.ENaC is a key element of the electrogenic sodium transport by kidney, colon andgland duct epithelia, thus maintaining blood Na+ and K+ levels and homeostasis [12], [5].