期刊
SCIENCE SIGNALING
卷 7, 期 352, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005450
关键词
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资金
- Royal Society [RG65196, RG69132]
- Biotechnology and Biological Sciences Research Council [BB/G013721/1]
- NIH [DA035926, DA023204, P30 DA13429]
- Biotechnology and Biological Sciences Research Council [BB/K000942/1, BB/G013721/1] Funding Source: researchfish
- BBSRC [BB/G013721/1, BB/K000942/1] Funding Source: UKRI
Four-domain voltage-gated Ca2+ and Na+ channels (Ca-V, Na-V) underpin nervous system function and likely emerged upon intragenic duplication of a primordial two-domain precursor. To investigate if two-pore channels (TPCs) may represent an intermediate in this evolutionary transition, we performed molecular docking simulations with a homology model of TPC1, which suggested that the pore region could bind antagonists of CaV or NaV. CaV or NaV antagonists blocked NAADP (nicotinic acid adenine dinucleotide phosphate)-evoked Ca2+ signals in sea urchin egg preparations and in intact cells that overexpressed TPC1. By sequence analysis and inspection of the model, we predicted a noncanonical selectivity filter in animal TPCs in which the carbonyl groups of conserved asparagine residues are positioned to coordinate cations. In contrast, a distinct clade of TPCs[TPCR(for TPC-related)] in several unicellular species had ion selectivity filters with acidic residues more akin to CaV. TPCRs were predicted to interact strongly with CaV antagonists. Our data suggest that acquisition of a blueprint pharmacological profile and changes in ion selectivity within four-domain voltage-gated ion channels may have predated intragenic duplication of an ancient two-domain ancestor.
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