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]
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]
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 |
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]
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]
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]
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]
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]
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]
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]
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 |
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]
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]
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]
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]
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]