Dataset Information

Cryo-EM micrographs of GABA(A)Rs purified from cells expressing human full-length alpha1, beta3 and gamma subunits, in presence of Ro15-4513 and megabody Mb38

ABSTRACT:

SUBMITTER: Andrija Sente

PROVIDER: EMPIAR-10912 | biostudies-other |

REPOSITORIES: biostudies-other

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Publications

Differential assembly diversifies GABAA receptor structures and signalling.

Sente Andrija A Desai Rooma R Naydenova Katerina K Malinauskas Tomas T Jounaidi Youssef Y Miehling Jonas J Zhou Xiaojuan X Masiulis Simonas S Hardwick Steven W SW Chirgadze Dimitri Y DY Miller Keith W KW Aricescu A Radu AR

Nature 20220330 7904

Type A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits1,2 and can be modulated by essential medicines including general anaesthetics and benzodiazepines3. Human GABAAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landsca ...[more]

PMID: 35355020

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Project description:The KCNMB3 gene encodes one of a family of four auxiliary beta subunits found in the mammalian genome that associate with Slo1 alpha subunits and regulate BK channel function. In humans, the KCNMB3 gene contains four N-terminal alternative exons that produce four functionally distinct beta3 subunits, beta3a-d. Three variants, beta3a-c, exhibit kinetically distinct inactivation behaviors. Since investigation of the physiological roles of BK auxiliary subunits will depend on studies in rodents, here we have determined the identity and functional properties of mouse beta3 variants. Whereas beta1, beta2, and beta4 subunits exhibit 83.2%, 95.3%, and 93.8% identity between mouse and human, the mouse beta3 subunit, excluding N-terminal splice variants, shares only 62.8% amino acid identity with its human counterpart. Based on an examination of the mouse genome and screening of mouse cDNA libraries, here we have identified only two N-terminal candidates, beta3a and beta3b, of the four found in humans. Both human and mouse beta3a subunits produce a characteristic use-dependent inactivation. Surprisingly, whereas the hbeta3b exhibits rapid inactivation, the putative mbeta3b does not inactivate. Furthermore, unlike hbeta3, the mbeta3 subunit, irrespective of the N terminus, mediates a shift in gating to more negative potentials at a given Ca(2+) concentration. The shift in gating gradually is lost following patch excision, suggesting that the gating shift involves some regulatory process dependent on the cytosolic milieu. Examination of additional genomes to assess conservation among splice variants suggests that the putative mbeta3b N terminus may not be a true orthologue of the hbeta3b N terminus and that both beta3c and beta3d appear likely to be primate-specific N-terminal variants. These results have three key implications: first, functional properties of homologous beta3 subunits may differ among mammalian species; second, the specific physiological roles of homologous beta3 subunits may differ among mammalian species; and, third, some beta3 variants may be primate-specific ion channel subunits.

Dataset Information

Cryo-EM micrographs of GABA(A)Rs purified from cells expressing human full-length alpha1, beta3 and gamma subunits, in presence of Ro15-4513 and megabody Mb38

Publications

Differential assembly diversifies GABA<sub>A</sub> receptor structures and signalling.

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