SCN9A Membrane Protein Introduction

Introduction of SCN9A

Sodium channel protein type 9 subunit alpha (SCN9A) is a 113.5-kb gene comprising 26 exons. It encodes a sodium channel which is composed of 1977 amino acids and is organized into 4 domains, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position. The SCNA family of sodium channels (SCN1A-SCN11A) evolved from an archetypal potassium channel by quadruplication, where four potassium subunits must coalesce to form the functional potassium channel.

Basic Information of SCN9A
Protein Name	Sodium channel protein type 9 subunit alpha
Gene Name	SCN9A
Aliases	Neuroendocrine sodium channel1 (hNE-Na1 Publication), Peripheral sodium channel 1 (PN1By), Sodium channel protein type IX subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.7
Organism	Homo sapiens (Human)
UniProt ID	Q15858
Transmembrane Times	24
Length (aa)	1988
Sequence	MAMLPPPGPQSFVHFTKQSLALIEQRIAERKSKEPKEEKKDDDEEAPKPSSDLEAGKQLPFIYGDIPPGMVSEPLEDLDPYYADKKTFIVLNKGKTIFRFNATPALYMLSPFSPLRRISIKILVHSLFSMLIMCTILTNCIFMTMNNPPDWTKNVEYTFTGIYTFESLVKILARGFCVGEFTFLRDPWNWLDFVVIVFAYLTEFVNLGNVSALRTFRVLRALKTISVIPGLKTIVGALIQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLKHKCFRNSLENNETLESIMNTLESEEDFRKYFYYLEGSKDALLCGFSTDSGQCPEGYTCVKIGRNPDYGYTSFDTFSWAFLALFRLMTQDYWENLYQQTLRAAGKTYMIFFVVVIFLGSFYLINLILAVVAMAYEEQNQANIEEAKQKELEFQQMLDRLKKEQEEAEAIAAAAAEYTSIRRSRIMGLSESSSETSKLSSKSAKERRNRRKKKNQKKLSSGEEKGDAEKLSKSESEDSIRRKSFHLGVEGHRRAHEKRLSTPNQSPLSIRGSLFSARRSSRTSLFSFKGRGRDIGSETEFADDEHSIFGDNESRRGSLFVPHRPQERRSSNISQASRSPPMLPVNGKMHSAVDCNGVVSLVDGRSALMLPNGQLLPEVIIDKATSDDSGTTNQIHKKRRCSSYLLSEDMLNDPNLRQRAMSRASILTNTVEELEESRQKCPPWWYRFAHKFLIWNCSPYWIKFKKCIYFIVMDPFVDLAITICIVLNTLFMAMEHHPMTEEFKNVLAIGNLVFTGIFAAEMVLKLIAMDPYEYFQVGWNIFDSLIVTLSLVELFLADVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQLFGKSYKECVCKINDDCTLPRWHMNDFFHSFLIVFRVLCGEWIETMWDCMEVAGQAMCLIVYMMVMVIGNLVVLNLFLALLLSSFSSDNLTAIEEDPDANNLQIAVTRIKKGINYVKQTLREFILKAFSKKPKISREIRQAEDLNTKKENYISNHTLAEMSKGHNFLKEKDKISGFGSSVDKHLMEDSDGQSFIHNPSLTVTVPIAPGESDLENMNAEELSSDSDSEYSKVRLNRSSSSECSTVDNPLPGEGEEAEAEPMNSDEPEACFTDGCVWRFSCCQVNIESGKGKIWWNIRKTCYKIVEHSWFESFIVLMILLSSGALAFEDIYIERKKTIKIILEYADKIFTYIFILEMLLKWIAYGYKTYFTNAWCWLDFLIVDVSLVTLVANTLGYSDLGPIKSLRTLRALRPLRALSRFEGMRVVVNALIGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYECINTTDGSRFPASQVPNRSECFALMNVSQNVRWKNLKVNFDNVGLGYLSLLQVATFKGWTIIMYAAVDSVNVDKQPKYEYSLYMYIYFVVFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGQDIFMTEEQKKYYNAMKKLGSKKPQKPIPRPGNKIQGCIFDLVTNQAFDISIMVLICLNMVTMMVEKEGQSQHMTEVLYWINVVFIILFTGECVLKLISLRHYYFTVGWNIFDFVVVIISIVGMFLADLIETYFVSPTLFRVIRLARIGRILRLVKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGMSNFAYVKKEDGINDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSKPPDCDPKKVHPGSSVEGDCGNPSVGIFYFVSYIIISFLVVVNMYIAVILENFSVATEESTEPLSEDDFEMFYEVWEKFDPDATQFIEFSKLSDFAAALDPPLLIAKPNKVQLIAMDLPMVSGDRIHCLDILFAFTKRVLGESGEMDSLRSQMEERFMSANPSKVSYEPITTTLKRKQEDVSATVIQRAYRRYRLRQNVKNISSIYIKDGDRDDDLLNKKDMAFDNVNENSSPEKTDATSSTTSPPSYDSVTKPDKEKYEQDRTEKEDKGKDSKESKK

Function of SCN9A Membrane Protein

The SCN9A or NaV1.7 channels are voltage-gated sodium channels expressed in dorsal root ganglia and sympathetic neurons. They mediate cellular excitability and are crucial players in gating pain transmission from the periphery to the central nervous system (CNS). Genetic and functional studies have shown that mutations in SCN9A are the major contributors to pain signaling and pain disorders in humans. Inactivating mutations in SCN9A, which cause loss-of-function of SCN9A channels, result in congenital insensitivity to pain, whereas gain-of-function mutations (single amino-acid substitutions) of SCN9A are linked to 3 pain syndromes: inherited erythromelalgia, paroxysmal extreme pain disorder, and idiopathic small nerve fiber neuropathy (I-SFN).

Fig.1 Location of characterized CIP and IEM-associated mutations in NaV1.7. Schematic representation of NaV1.7 showing the 24 transmembrane (TM) domains contained within four regions (DI-IV). (Emery, 2015)

Application of SCN9A Membrane Protein in Literature

Emery E.C., et al. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations. Journal of Neuroscience. 2015, 35(20):7674-81. PubMed ID: 25995458

This article finds complex genotype-phenotype correlations that exist in SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.
Koenig J., et al. Regulation of Nav1.7: A conserved SCN9A natural antisense transcript expressed in dorsal root ganglia. PLoS One. 2015, 10(6): e0128830. PubMed ID: 26035178

This article suggests that SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.
Li Q.S., et al. SCN9A variants may be implicated in neuropathic pain associated with diabetic peripheral neuropathy and pain severity. Clinical Journal of Pain. 2015, 31(11):976-82. PubMed ID: 25585270

This article suggests a role of SCN9A in the disease etiology of neuropathic pain.
Duan G., et al. The effect of SCN9A variation on basal pain sensitivity in the general population: An experimental study in young women. Journal of Pain. 2015, 16(10):971-80. PubMed ID: 26168879

This article reveals that SCN9A SNPs in basal pain perception may lead to more individualized pain treatment for young women in the future.
Meijer I.A., et al. An atypical case of SCN9A mutation presenting with global motor delay and a severe pain disorder. Muscle Nerve. 2014, 49(1):134-8. PubMed ID: 23893323

This article identifies a de novo missense mutation in the S4-5 linker of the first domain of the Nav1.7 channel in a patient with early-onset paroxysmal pain attacks and erythema involving the hands, feet, and perineal area, suggesting an overlap PE/PEPD phenotype.

SCN9A Preparation Options

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Reference

Emery E C, et al. (2015). Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations. Journal of Neuroscience. 35(20): 7674-81.

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