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Identification of residues in the first transmembrane domain of the P2X7 that regulates receptor trafficking, sensitization, and dye uptake function

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F23%3A00573688" target="_blank" >RIV/67985823:_____/23:00573688 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11310/23:10465261 RIV/00216208:11110/23:10465261

  • Result on the web

    <a href="https://doi.org/10.1111/jnc.15813" target="_blank" >https://doi.org/10.1111/jnc.15813</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1111/jnc.15813" target="_blank" >10.1111/jnc.15813</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Identification of residues in the first transmembrane domain of the P2X7 that regulates receptor trafficking, sensitization, and dye uptake function

  • Original language description

    P2X receptors (P2X1-7) are trimeric ion channels activated by extracellular ATP. Each P2X subunit contains two transmembrane helices (TM1 and TM2). We substituted all residues in TM1 of rat P2X7 with alanine or leucine one by one, expressed mutants in HEK293T cells, and examined the pore permeability by recording both membrane currents and fluorescent dye uptake in response to agonist application. Alanine substitution of G27, K30, H34, Y40, F43, L45, M46, and D48 inhibited agonist-stimulated membrane current and dye uptake, and all but one substitution, D48A, prevented surface expression. Mutation V41A partially reduced both membrane current and dye uptake, while W31A and A44L showed reduced dye uptake not accompanied by reduced membrane current. Mutations T28A, I29A, and L33A showed small changes in agonist sensitivity, but they had no or small impact on dye uptake function. Replacing charged residues with residues of the same charge (K30R, H34K, and D48E) rescued receptor function, while replacement with residues of opposite charge inhibited (K30E and H34E) or potentiated (D48K) receptor function. Prolonged stimulation with agonist-induced current facilitation and a leftward shift in the dose–response curve in the P2X7 wild-type and most functional mutants, but sensitization was absent in the W31A, L33A, and A44L. Detailed analysis of the decay of responses revealed two kinetically distinct mechanisms of P2X7 deactivation: fast represents agonist unbinding, and slow might represent resetting of the receptor to the resting closed state. These results indicate that conserved and receptor-specific TM1 residues control surface expression of the P2X7 protein, non-polar residues control receptor sensitization, and D48 regulates intrinsic channel properties.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30105 - Physiology (including cytology)

Result continuities

  • 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

Others

  • Publication year

    2023

  • Confidentiality

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

Data specific for result type

  • Name of the periodical

    Journal of Neurochemistry

  • ISSN

    0022-3042

  • e-ISSN

    1471-4159

  • Volume of the periodical

    165

  • Issue of the periodical within the volume

    6

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    18

  • Pages from-to

    874-891

  • UT code for WoS article

    000975924700001

  • EID of the result in the Scopus database

    2-s2.0-85153501523