Delineation of the functional properties exhibited by the Zinc-Activated Channel (ZAC) and its high-frequency Thr(128)Ala variant (rs2257020) in Xenopus oocytes
| Autor: | Nawid Madjroh, Uffe Kristiansen, Pella Cecilia Söderhielm, Joshua L. Smalley, Anders A. Jensen, Paul Davies |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cell Xenopus Cys-loop receptor Enzyme-Linked Immunosorbent Assay Polymorphism Single Nucleotide Article Ion Channels 03 medical and health sciences Xenopus laevis 0302 clinical medicine High-frequency variation Polymorphism (computer science) In vivo Single nucleotide polymorphism (SNP) TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY medicine Animals Immunoprecipitation Receptor Pharmacology biology Chemistry HEK 293 cells Transfection Two-electrode voltage clamp electrophysiology biology.organism_classification Zinc-Activated Channel (ZAC) Cell biology Electrophysiology Zinc 030104 developmental biology medicine.anatomical_structure Pentameric ligand-gated ion channel 030220 oncology & carcinogenesis Oocytes |
| Zdroj: | Pharmacol Res Madjroh, N, Davies, P A, Smalley, J L, Kristiansen, U, Söderhielm, P C & Jensen, A A 2021, ' Delineation of the functional properties exhibited by the Zinc-Activated Channel (ZAC) and its high-frequency Thr 128 Ala variant (rs2257020) in Xenopus oocytes ', Pharmacological Research, vol. 169, 105653 . https://doi.org/10.1016/j.phrs.2021.105653 |
| Popis: | The signalling characteristics of the Zinc-Activated Channel (ZAC), a member of the Cys-loop receptor (CLR) superfamily, are presently poorly elucidated. The ZACN polymorphism c.454G>A encoding for the Thr128Ala variation in ZAC is found in extremely high allele frequencies across ethnicities. In this, the first study of ZAC in Xenopus oocytes by TEVC electrophysiology, ZACThr128 and ZACAla128 exhibited largely comparable pharmacological and signalling characteristics, but interestingly the Zn2+- and H+-evoked current amplitudes in ZACAla128-oocytes were dramatically smaller than those in ZACThr128-oocytes. While the variation thus appeared to impact cell surface expression and/or channel properties of ZAC, the similar expression properties exhibited by ZACThr128 and ZACAla128 in transfected mammalian cells indicated that their distinct functionalities could arise from the latter. In co-expression experiments, wild-type and variant ZAC subunits assembled efficiently into “heteromeric” complexes in HEK293 cells, while the concomitant presence of ZACAla128 in ZACThr128:ZACAla128-oocytes did not exert a dominant negative effect on agonist-evoked current amplitudes compared to those in ZACThr128-oocytes. Finally, the structural determinants of the functional importance of the 1-hydroxyethyl side-chain of Thr128 appeared to be subtle, as agonist-evoked current amplitudes in ZACSer128-, ZACVal128- and ZACIle128-oocytes also were substantially lower than those in ZACThr128-oocytes. In conclusion, the functional properties exhibited by ZAC in this work substantiate the notion of it being an atypical CLR. While the impact of the Thr128Ala variation on ZAC functionality in oocytes is striking, it remains to be investigated whether and to which extent this translates into an in vivo setting and thus could constitute a source of inter-individual variation in ZAC physiology. |
| Databáze: | OpenAIRE |
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