Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population
TRPP3 (also called PKD2L1) is a nonselective, cation-permeable channel activated by multiple stimuli, including extracellular pH changes. TRPP3 had been considered a candidate for sour sensor in humans, due to its high expression in a subset of tongue receptor cells detecting sour, along with its membership to the TRP channel family known to function as sensory receptors. Here, we describe the functional consequences of two non-synonymous genetic variants (R278Q and R378W) found to be under strong positive selection in an Ethiopian population, the Gumuz. Electrophysiological studies and 3D modelling reveal TRPP3 loss-of-functions produced by both substitutions. R278Q impairs TRPP3 activation after alkalinisation by mislocation of H+ binding residues at the extracellular polycystin mucolipin domain. R378W dramatically reduces channel activity by altering conformation of the voltage sensor domain and hampering channel transition from closed to open state. Sour sensitivity tests in R278Q/R378W carriers argue against both any involvement of TRPP3 in sour detection and the role of such physiological process in the reported evolutionary positive selection past event.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
Scientific reports - 10(2020), 1 vom: 02. Dez., Seite 20999 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Walsh, Sandra [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Calcium Channels |
|---|
| Anmerkungen: |
Date Completed 14.01.2021 Date Revised 14.01.2021 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-020-78081-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM318349744 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM318349744 | ||
| 003 | DE-627 | ||
| 005 | 20231226202258.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-020-78081-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1061.xml |
| 035 | |a (DE-627)NLM318349744 | ||
| 035 | |a (NLM)33268808 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Walsh, Sandra |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.01.2021 | ||
| 500 | |a Date Revised 14.01.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a TRPP3 (also called PKD2L1) is a nonselective, cation-permeable channel activated by multiple stimuli, including extracellular pH changes. TRPP3 had been considered a candidate for sour sensor in humans, due to its high expression in a subset of tongue receptor cells detecting sour, along with its membership to the TRP channel family known to function as sensory receptors. Here, we describe the functional consequences of two non-synonymous genetic variants (R278Q and R378W) found to be under strong positive selection in an Ethiopian population, the Gumuz. Electrophysiological studies and 3D modelling reveal TRPP3 loss-of-functions produced by both substitutions. R278Q impairs TRPP3 activation after alkalinisation by mislocation of H+ binding residues at the extracellular polycystin mucolipin domain. R378W dramatically reduces channel activity by altering conformation of the voltage sensor domain and hampering channel transition from closed to open state. Sour sensitivity tests in R278Q/R378W carriers argue against both any involvement of TRPP3 in sour detection and the role of such physiological process in the reported evolutionary positive selection past event | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Calcium Channels |2 NLM | |
| 650 | 7 | |a PKD2L1 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, Cell Surface |2 NLM | |
| 700 | 1 | |a Izquierdo-Serra, Mercè |e verfasserin |4 aut | |
| 700 | 1 | |a Acosta, Sandra |e verfasserin |4 aut | |
| 700 | 1 | |a Edo, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a Lloret, María |e verfasserin |4 aut | |
| 700 | 1 | |a Moret, Roser |e verfasserin |4 aut | |
| 700 | 1 | |a Bosch, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Oliva, Baldo |e verfasserin |4 aut | |
| 700 | 1 | |a Bertranpetit, Jaume |e verfasserin |4 aut | |
| 700 | 1 | |a Fernández-Fernández, José Manuel |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 10(2020), 1 vom: 02. Dez., Seite 20999 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2020 |g number:1 |g day:02 |g month:12 |g pages:20999 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-020-78081-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2020 |e 1 |b 02 |c 12 |h 20999 | ||