Paralytic (gene)

Last updated
Paralytic
Identifiers
Symbolpara
Alt. symbolsbss, sbl, olfD, DmNav, DmNav1, DmNav
NCBI gene 32619
UniProt P35500
Other data
Locus Chr. X 16,455,230 - 16,533,368
Search for
Structures Swiss-model
Domains InterPro

Paralytic is a gene in the fruit fly, Drosophila melanogaster , which encodes a voltage gated sodium channel within D. melanogaster neurons. [1] This gene is essential for locomotive activity in the fly. [1] There are 9 different para alleles, composed of a minimum of 26 exons within over 78kb [2] of genomic DNA. [3] The para gene undergoes alternative splicing to produce subtypes of the channel protein. [3] Flies with mutant forms of paralytic are used in fly models of seizures, since seizures can be easily induced in these flies. [4]

Contents

Gene

The para gene is located on the X chromosome within the Drosophila genome. [5] There are 26 para exons, 13 are constitutively expressed in the transcript, while 15 are alternatively spliced. [6] Alternative splicing allows for the formation of 60 unique transcripts and 57 unique polypeptides. [6] The independent splicing of 11 exons allows for the unique cytoplasmic loops, the alternative splicing also can effect the Na+ channel kinetics, [6] such as the varying gating conductivities. [1] The mature mRNA transcript only includes one of C or D exonic region and only one of K or L exonic region, as they code for the same or similar regions. [6] Neurons containing para exon L, show an increase in firing frequency which is associated with increase seizure susceptibility. [6] Channel kinetics are influenced by splicing, that not only changes protein structure but can allow for varying modifications, like differential binding of cofactors. [7]

Known mutant variants

Currently there are 117 known allele variants within the para locus, [6] a few are mentioned below.

MutantPropertiesMutationPhenotype
parabss1gain-of-functionmis-sense substitution in S3 of HD4leads to seizures
paraGEFS+sustained depolarization in GABA neuronsK→T knock-in at S2 of HD2temperature susceptibility for seizures
paraDSreduction in Na+ currentS→R knock-in at S1 of HD2temperature susceptibility for seizures
paraJSreduction of transcriptiontransposon insertion 3' UTR seizure-suppressor

Protein

This proteins forms a sodium-selective ion channel, that relies on an electrochemical gradient. [1] The protein consists of four homology domains, HD1, HD2, HD3 and HD4. Each homology domain has six alpha helical segments, S1-S6. [6] The small alpha-helical region between S5 and S6 is known as the channel pore. Mutations within this region may be responsible for ion selectivity. [6] The cytoplasmic loop between HD3 and HD4 is responsible for fast inactivation and blocking conductance. [6] The voltage sensor 4 in HD III is partially formed by exon L and K. [7] The alternative splicing at this locus causes a difference in the charged current at this channel. [7] Exon L produces 8% of the transient current, which falls to 2% when the K exon is incorporated. [7]

This image depicts the a-subunit of a generic voltage-gated sodium channel and displays the six alpha helical segments (S1-S6) per homology domains (I - IV). Alphasubunit sodium channel.png
This image depicts the α-subunit of a generic voltage-gated sodium channel and displays the six alpha helical segments (S1-S6) per homology domains (I - IV).

Function

Paralytic encodes a protein channel which transfers sodium ions into neurons and is activated in response to changes in the voltage across a membrane [1] to propagate an action potential. [3] The paralytic protein has been found in the thoracic-abdominal ganglion, eye tissues and cortical regions in the brain. [1]

Role in seizure models

Flies with certain mutations in para gene are used as models for studying seizures and epilepsy, as they are much more prone to seizures than regular flies. [4] Some of these mutant para genotypes are cause either severe sensitivity to seizures, or act as seizure suppressors. [6] In these mutant flies, seizures can be induced by mechanical shock, electrical shock, or high-frequency visual stimuli such as strobe lights.

A number of mutations in paralytic have been described which can cause this increased sensitivity to seizures. Some of these, such as bss1 and bss2 can be caused by a single point mutation in the paralytic gene which makes the channel less able to inactivate itself after being activated. [4]

Understanding the genetic and environmental influences on the seizures in mutant para flies, has proved to be a trackable system in understanding the complexity in human seizure models. [6]

Evolution

Voltage-gated sodium channels are highly conserved across lineages. The exons in specific, are conserved across many diverged groups of species, this seems to indicate physiological importance. [7] Insect species have only one a single sodium channel gene which encodes the mammalian equivalent of α subunit. Insects like D. melanogaster take advantage of alternative splicing and RNA editing to generate distinct gating properties of sodium channels. [8]

Human orthologs

The most closely related genes to paralytic in humans are SCN1A, SCN8A and SCN2A, all of which are genes that encode sodium channels. [1] [6] Mutations in the human orthologs have been linked to seizure disorders and cognitive defects. [9] Fly models can be used to study branches of human epilepsy, by using GEFS+ mutations at SCN1A gene for knock-in's at the para locus in D. melanogaster. [6]

See also

Related Research Articles

<i>Drosophila melanogaster</i> Species of fruit fly

Drosophila melanogaster is a species of fly in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Charles W. Woodworth's 1901 proposal of the use of this species as a model organism, D. melanogaster continues to be widely used for biological research in genetics, physiology, microbial pathogenesis, and life history evolution. As of 2017, five Nobel Prizes have been awarded to drosophilists for their work using the insect.

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs usually contain differences in their amino acid sequence and, often, in their biological functions.

<span class="mw-page-title-main">Synonymous substitution</span>

A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change ("voltage-gated", "voltage-sensitive", or "voltage-dependent" sodium channel; also called "VGSCs" or "Nav channel") or a binding of a substance (a ligand) to the channel (ligand-gated sodium channels).

The shaker (Sh) gene, when mutated, causes a variety of atypical behaviors in the fruit fly, Drosophila melanogaster. Under ether anesthesia, the fly’s legs will shake ; even when the fly is unanaesthetized, it will exhibit aberrant movements. Sh-mutant flies have a shorter lifespan than regular flies; in their larvae, the repetitive firing of action potentials as well as prolonged exposure to neurotransmitters at neuromuscular junctions occurs.

<span class="mw-page-title-main">PAX6</span> Protein-coding gene in the species Homo sapiens

Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene.

The fruitless gene (fru) is a Drosophila melanogaster gene that encodes several variants of a putative transcription factor protein. Normal fruitless function is required for proper development of several anatomical structures necessary for courtship, including motor neurons which innervate muscles needed for fly sexual behaviors. The gene does not have an obvious mammalian homolog, but appears to function in sex determination in species as distant as the mosquito Anopheles gambiae.

Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood. GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravet's syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.

Na<sub>v</sub>1.4 Protein-coding gene in the species Homo sapiens

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

SCN5A

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

Na<sub>v</sub>1.9 Protein-coding gene in the species Homo sapiens

Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.

SCN1A

Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

SCN2A

Sodium channel protein type 2 subunit alpha , is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain sodium channel protein type 2 subunit alpha are sometimes called Nav1.2 channels.

<span class="mw-page-title-main">SCN1B</span> Protein-coding gene in the species Homo sapiens

Sodium channel subunit beta-1 is a protein that in humans is encoded by the SCN1B gene.

<span class="mw-page-title-main">SCN3A</span> Protein-coding gene in humans

Sodium channel, voltage-gated, type III, alpha subunit (SCN3A) is a protein that in humans is encoded by the SCN3A gene.

<span class="mw-page-title-main">SCN8A</span>

Sodium channel protein type 8 subunit alpha also known as Nav1.6 is a membrane protein encoded by the SCN8A gene. Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at each node of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.

<span class="mw-page-title-main">60S ribosomal protein L38</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">KCNH5</span>

Potassium voltage-gated channel, subfamily H (eag-related), member 5, also known as KCNH5, is a human gene encoding the Kv10.2 protein.

<span class="mw-page-title-main">Lawrence B. Salkoff</span> American neuroscientist (born 1944)

Lawrence B. Salkoff is an American neuroscientist and currently a professor of neuroscience and genetics at Washington University School of Medicine

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

References

  1. 1 2 3 4 5 6 7 "Dmel\para". FlyBase. Retrieved 28 March 2017.
  2. ↑ "D. melanogaster chrX:16,455,230-16,533,368 - UCSC Genome Browser v357". genome.ucsc.edu. Retrieved 2017-11-22.
  3. 1 2 3 Loughney K, Kreber R, Ganetzky B (September 1989). "Molecular analysis of the para locus, a sodium channel gene in Drosophila". Cell. 58 (6): 1143–54. doi:10.1016/0092-8674(89)90512-6. PMID   2550145. S2CID   8375638.
  4. 1 2 3 Parker L, Padilla M, Du Y, Dong K, Tanouye MA (February 2011). "Drosophila as a model for epilepsy: bss is a gain-of-function mutation in the para sodium channel gene that leads to seizures". Genetics. 187 (2): 523–34. doi:10.1534/genetics.110.123299. PMC   3030494 . PMID   21115970.
  5. ↑ "para paralytic [Drosophila melanogaster (fruit fly)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-22.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 Kroll JR, Saras A, Tanouye MA (December 2015). "Drosophila sodium channel mutations: Contributions to seizure-susceptibility". Experimental Neurology. 274 (Pt A): 80–7. doi:10.1016/j.expneurol.2015.06.018. PMC   4644469 . PMID   26093037.
  7. 1 2 3 4 5 Lin WH, Wright DE, Muraro NI, Baines RA (September 2009). "Alternative splicing in the voltage-gated sodium channel DmNav regulates activation, inactivation, and persistent current". Journal of Neurophysiology. 102 (3): 1994–2006. doi:10.1152/jn.00613.2009. PMC   2746785 . PMID   19625535.
  8. ↑ "Paralytic". www.sdbonline.org. Retrieved 2017-11-22.
  9. ↑ Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, Erickson RP, Hammer MF (March 2012). "De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP". American Journal of Human Genetics. 90 (3): 502–10. doi:10.1016/j.ajhg.2012.01.006. PMC   3309181 . PMID   22365152.
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