''Paralytic'' is a gene in the fruit fly, ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...

'', which encodes a voltage gated

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

within ''D. melanogaster'' neurons. This gene is essential for locomotive activity in the fly. There are 9 different ''para''

alleles An allele is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule. Alleles can differ at a single position through single nucleotide polymorphisms (SNP), but they can also have insertions and deletions ...

, composed of a minimum of 26

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s within over 78kb of genomic DNA. The ''para'' gene undergoes

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

to produce subtypes of the channel protein. Flies with mutant forms of ''paralytic'' are used in fly models of

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s, since seizures can be easily induced in these flies.

Gene

The ''para'' gene is located on the X chromosome within the Drosophila genome. There are 26 ''para'' exons, 13 are constitutively expressed in the transcript, while 15 are alternatively spliced.

Alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

allows for the formation of 60 unique transcripts and 57 unique polypeptides. The independent splicing of 11 exons allows for the unique cytoplasmic loops, the alternative splicing also can effect the Na⁺ channel kinetics, such as the varying gating conductivities. The

mature mRNA Mature messenger RNA, often abbreviated as mature mRNA is a eukaryotic RNA transcript that has been spliced and processed and is ready for translation in the course of protein synthesis. Unlike the eukaryotic RNA immediately after transcription ...

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. Neurons containing ''para'' exon L, show an increase in firing frequency which is associated with increase seizure susceptibility. Channel kinetics are influenced by splicing, that not only changes protein structure but can allow for varying modifications, like differential binding of cofactors.

Known mutant variants

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

Protein

This proteins forms a sodium-selective ion channel, that relies on an electrochemical gradient. The protein consists of four homology domains, HD1, HD2, HD3 and HD4. Each homology domain has six

alpha helical An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

segments, S1-S6. 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. The cytoplasmic loop between HD3 and HD4 is responsible for fast inactivation and blocking conductance. The voltage sensor 4 in HD III is partially formed by exon L and K. The alternative splicing at this locus causes a difference in the charged current at this channel. Exon L produces 8% of the transient current, which falls to 2% when the K exon is incorporated. Alphasubunit sodium channel

Function

''Paralytic'' encodes a protein channel which transfers

sodium ions Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...

into neurons and is activated in response to changes in the

voltage Voltage, also known as (electrical) potential difference, electric pressure, or electric tension, is the difference in electric potential between two points. In a Electrostatics, static electric field, it corresponds to the Work (electrical), ...

across a membrane to propagate an

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

. The paralytic protein has been found in the thoracic-abdominal ganglion, eye tissues and cortical regions in the brain.

Role in seizure models

Flies with certain mutations in ''para'' gene are used as models for studying seizures and

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, as they are much more prone to seizures than regular flies. Some of these mutant ''para'' genotypes are cause either severe sensitivity to seizures, or act as seizure suppressors. 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. 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.

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. 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

and

RNA editing RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms ...

to generate distinct gating properties of sodium channels.

Human orthologs

The most closely related genes to ''paralytic'' in humans are

SCN1A Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the ''SCN1A'' gene. Gene location The ''SCN1A'' gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6 ...

SCN8A 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 h ...

and SCN2A, all of which are genes that encode sodium channels. Mutations in the human orthologs have been linked to seizure disorders and cognitive defects. 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''.

References

{{Reflist Drosophila melanogaster genes Ion channels