Paralytic (gene)
From Wikipedia - Reading time: 5 min
| Paralytic | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | para | ||||||
| Alt. symbols | bss, sbl, olfD, DmNav, DmNav1, DmNav | ||||||
| NCBI gene | 32619 | ||||||
| UniProt | P35500 | ||||||
| Other data | |||||||
| Locus | Chr. X 16,455,230 - 16,533,368 | ||||||
| |||||||
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]
Gene
[edit]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
[edit]Currently there are 117 known allele variants within the para locus,[6] a few are mentioned below.
| Mutant | Properties | Mutation | Phenotype |
|---|---|---|---|
| parabss1 | gain-of-function | mis-sense substitution in S3 of HD4 | leads to seizures |
| paraGEFS+ | sustained depolarization in GABA neurons | K→T knock-in at S2 of HD2 | temperature susceptibility for seizures |
| paraDS | reduction in Na+ current | S→R knock-in at S1 of HD2 | temperature susceptibility for seizures |
| paraJS | reduction of transcription | transposon insertion 3' UTR | seizure-suppressor |
Protein
[edit]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]
Function
[edit]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
[edit]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
[edit]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
[edit]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
[edit]References
[edit]- ^ a b c d e f g "Dmel\para". FlyBase. Retrieved 28 March 2017.
- ^ "D. melanogaster chrX:16,455,230-16,533,368 - UCSC Genome Browser v357". genome.ucsc.edu. Retrieved 2017-11-22.
- ^ a b c 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.
- ^ a b c 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.
- ^ "para paralytic [Drosophila melanogaster (fruit fly)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-22.
- ^ a b c d e f g h i j k l m 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.
- ^ a b c d e 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.
- ^ "Paralytic". www.sdbonline.org. Retrieved 2017-11-22.
- ^ 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.
EncycloReader
is supported by the 
KSF