User:DBM393/sandbox

 Ideas and things: 

Make history of TRP channels and Drosophilia a sub group

Add to the structure of TRP channels

Add permeability

 Possible References: 

1.) TRP channels and light sensitivity in drosophilia: https://www.sciencedirect.com/science/article/pii/S1350946217301222

2.) (good) TRP channels and disease: https://www.physiology.org/doi/full/10.1152/physrev.00021.2006

3.) TRP channels and metabolic disorders: https://onlinelibrary.wiley.com/doi/full/10.1111/obr.12703

4.) TRP channel expression during pregnancy: https://www.sciencedirect.com/science/article/pii/S0167488918302519

5.) TRP channels and cancer: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027473/

6.) (used basic function) Overview of TRP channels: https://www.annualreviews.org/doi/10.1146/annurev.biochem.75.103004.142819

7.) (good) TRP channels and pain: https://www.annualreviews.org/doi/10.1146/annurev-cellbio-101011-155833

8.) (good) TRP channels and pain relief: https://www.sciencedirect.com/science/article/pii/S0014299913001738

9.) (used basic function) The transient receptor potential family of ion channels: https://genomebiology.biomedcentral.com/track/pdf/10.1186/gb-2011-12-3-218?site=genomebiology.biomedcentral.com

10.) (used structure and basic function) TRP Channels as Therapeutic Targets (book): https://www.sciencedirect.com/science/article/pii/B9780124200241000011

11.) (good TRPY and history) The History of TRP Channels a commentary and reflection: https://link.springer.com/article/10.1007/s00424-010-0920-3

12.) (used structure and TRPY) Evolutionary dynamics of metazoan TRP channels: https://link.springer.com/article/10.1007/s00424-015-1705-5

13.) (used) Ion Channels of excitable membranes, 3rd E

14.) (good TRPY) Ancestral Ca2+ Signaling Machinery in Early Animal and Fungal Evolution: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037924/

Sub-families
In the TRP super-family there are currently 7 different sub-families split into two groups. Group one consists of TRPC, TRPV, TRPA, TRPM, and TRPN. While group two contains TRPP and TRPML. There is an eighth sub-family labeled TRPY that is not included in either of these groups because of its distant relation. All of these sub-families are similar in that they are molecular sensing, non-selective cation channels that have six transmembrane segments, however, each sub-family is very unique and shares little structural homology with one another. This uniqueness gives rise to the various sensory perception and regulation functions that TRP channels have throughout the body. Group one and group two vary in that both TRPP and TRPML of group two have a much longer extracellular loop between the S1 and S2 transmembrane segments. Another differentiating characteristic is that all the group one sub-families either contain a C-terminal, intracellular ankyrin repeat sequence, an N-terminal TRP domain sequence, or both--whereas both group two sub-families have neither. Below are members of the sub-families and a brief description of each: TRPC, C for "canonical", is named for being the most closely related to TRP channels in drosophilia, sharing above 30% amino acid homology. There are actually only six TRPC channels expressed in humans because TRPC2 is found to be expressed solely in mice and is considered a pseudo-gene in humans; this is partly due to the role of TRPC2 in detecting pheromones, which mice have an increased ability compared to humans. Mutations in TRPC channels have been associated with respiratory diseases along with focal segmental glomerulosclerosis in the kidneys. All TRPC channels are activated either by phospholipase C (PLC) or diacyglycerol (DAG). TRPV, V for "vanilloid", is named for the vanilloid chemicals that activate this channel, and are some of the most studied TRP channels. These channels have been made famous for their association with molecules such as capsaicin (a TRPV1 agonist), and its ability to produce heat sensation and act as a topical ointment for pain relief. TRPA, A for "ankyrin", is named for the large amount of ankyrin repeats found near the N-terminus. TRPA is primarily found in afferent nociceptive nerve fibers and is associated with the amplification of pain signaling as well as cold pain hypersensitivity. These channels have been shown to be both mechanical receptors for pain and chemosensors activated by various chemical species, including isothiocyanates (pungent chemicals in substances such as mustard oil and wasabi), cannabinoids, general and local analgesics, and cinnamaldehyde. TRPM, M for "melastatin", was found during a comparative genetic analysis between benign nevi and malignant nevi (melanoma). Mutatations within TRPM channels have been associated with hypomagnesemia with secondary hypocalcemia. TRPM channels have also become famous for their cold-sensing mechanisms, such is the case with TRPM8. TRPN, N for "no mechanoreceptor potential C" or "NOMPC", are not found in mammals and have been shown only to be expressed in zebrafish, worms, and flies. There is more to be discovered as to what TRPN does, however, it is thought to be mechanically gated. TRPP, P for "polycistin", is named for polycystic kidney disease that is associated with this channel. These channels are also referred to as PKD (polycistic kindey disease) ion channels.

TRPML, ML for "mucolipin", gets its name from the neurodevelopmental disorder mucolipidosis IV. Mucolipidosis IV was first discovered in 1974 by E.R. Berman who noticed abnormalities in the eyes of an infant. These abnormalities soon became associated with mutations to the MCOLN1 gene which encodes for the TRPML1 ion channel. TRPML is still not highly characterized.

TRPY1

TRPY1, Y for "yeast", is highly localized to the yeast vacuole, which is the functional equivalent of a lysosome in a mammalian cell, and acts as a mechanosensor for vacuolar osmotic pressure. Patch clamp techniques and hyperosmotic stimulation have illustrated that TRPY plays a role in intracellular calcium release. Phylogenetic analysis has shown that TRPY1 does not form a part with the other metazoan TRP groups one and two, and is suggested to have evolved after the divergence of metazoans and fungi.

Structure
TRP channels are composed of 6 membrane-spanning helices (S1-S6) with intracellular N- and C-termini. Mammalian TRP channels are activated and regulated by a wide variety of stimuli including many post-transcriptional mechanisms like phosphorylation, G-protein receptor coupling, ligand-gating, and ubiquitination. The receptors are found in almost all cell types and are largely localized in cell and organelle membranes, modulating ion entry.

Most TRP channels form homo- or heterotetramers when completely functional. The ion selectivity filter, pore, is formed by the complex combination of p-loops in the tetrameric protein, which are situated in the extracellular domain between the S5 and S6 transmembrane segments. As with most cation channels, TRP channels have negatively charged residues within the pore to attract the positively charged ions.

Group 1 Characteristics
Each channel in this group is structurally unique that add to the diversity of functions that TRP channels possess, however, there are some commonalities that distinguish this group from others. Starting from the intracellular N-terminus there are varying lengths of ankryin repeats (except in TRPM) that aid with membrane anchoring and other protein interactions. Shortly following S6 on the C-terminal end, there is a highly conserved TRP domain (except in TRPA) which is involved with gating modulation and channel mulitmerization. Other C-terminal modifications such as alpha-kinase domains in TRPM7 and M8 have been seen as well in this group.

Group 2 Characteristics
Group two most distinguishable trait is the long extracellular span between the S1 and S2 transmembrane segments. Members of group two are also lacking in ankryin repeats and a TRP domain. They have been shown, however, to have endoplasmic reticulum (ER) retention sequences towards on the C-terminal end illustrating possible interactions with the ER.