Cytoplasmic inter-subunit interface modulates TRPC5 activity: Molecular mechanism behind intellectual disability-related R175C mutation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F25%3A00639084" target="_blank" >RIV/67985823:_____/25:00639084 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1016/j.nbd.2025.107082" target="_blank" >https://doi.org/10.1016/j.nbd.2025.107082</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.nbd.2025.107082" target="_blank" >10.1016/j.nbd.2025.107082</a>

Result language

angličtina

Original language name

Cytoplasmic inter-subunit interface modulates TRPC5 activity: Molecular mechanism behind intellectual disability-related R175C mutation

Original language description

The TRPC5 (Transient Receptor Potential Canonical 5) receptor, which is highly expressed in the brain, kidney, and sensory neurons, is emerging as a pharmacological target due to its involvement in renal physiology, pain, metabolic homeostasis, and various neurodevelopmental disorders. The recently identified R175C mutation associated with intellectual disability and autism spectrum disorders has supported the critical importance of TRPC5 for central nervous system function. Compared to other neuronal TRPs, TRPC5 remains understudied, with its activation mechanisms not well understood. Here, we focused on elucidating the molecular mechanisms of TRPC5 gating that are impaired by the R175C mutation. Based on the structural analyses and bioinformatics profiling, we recognized R175 as part of an inter-subunit interface involved in various modes of TRPC5 gating. Using molecular simulations, site-directed mutagenesis and electrophysiological measurements, we identified that a unique evolutionarily conserved region (dubbed zero-tolerance) contributes to the dynamic network of hydrogen bonds at this interface. Our data show that while the stability of the closed conformation is associated with more contacts at the lower part (Q309) of the zero-tolerance region, fewer contacts here and more at the upper part (R323) apparently accompany the open conformation. Moreover, the activity of TRPC5 can be tuned from this interface by cellular processes, as it is a site of post-translational modification, including putative phosphorylation at S193. In conclusion, our results characterize the molecular mechanism underlying the functional impairment associated with the R175C mutation and provide a possible explanation for the functional importance of the zero-tolerance region in TRPC5.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10610 - Biophysics

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Neurobiology of Disease

ISSN

0969-9961

e-ISSN

1095-953X

Volume of the periodical

215

Issue of the periodical within the volume

15 Oct

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

11

Pages from-to

107082

UT code for WoS article

001567490300001

EID of the result in the Scopus database

2-s2.0-105014964898