{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:41:49Z","timestamp":1791286909745,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T00:00:00Z","timestamp":1402358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1034642"],"award-info":[{"award-number":["1034642"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,7]]},"abstract":"Background and Purpose<\/jats:title>\u03c9\u2010Conotoxins CVIE<\/jats:styled-content> and CVIF<\/jats:styled-content> (CVIE<\/jats:styled-content>&F<\/jats:styled-content>) selectively inhibit Cav<\/jats:sub><\/jats:styled-content>2.2 channels and are lead molecules in the development of novel analgesics. At physiological membrane potentials, CVIE<\/jats:styled-content>&F<\/jats:styled-content> block of Cav<\/jats:sub><\/jats:styled-content>2.2 channels is weakly reversible. To improve reversibility, we designed and synthesized arginine CVIE<\/jats:styled-content>&F<\/jats:styled-content> analogues in which arginine was substituted for lysine at position 10 ([R10K<\/jats:styled-content>]CVIE<\/jats:styled-content>&F<\/jats:styled-content>), and investigated their serum stability and pharmacological actions on voltage\u2010gated calcium channels (VGCCs<\/jats:styled-content>).<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Changes in peptide structure due to R10K<\/jats:styled-content> substitution were assessed by NMR<\/jats:styled-content>. Peptide stability in human serum was analysed by reversed\u2010phase HPLC<\/jats:styled-content> and MS<\/jats:styled-content> over a 24\u2009h period. Two\u2010electrode voltage\u2010clamp and whole\u2010cell patch clamp techniques were used to study [R10K<\/jats:styled-content>]CVIE<\/jats:styled-content>&F<\/jats:styled-content> effects on VGCC<\/jats:styled-content> currents in X<\/jats:italic><\/jats:styled-content>enopus<\/jats:italic> oocytes and rat dorsal root ganglion neurons respectively.<\/jats:p><\/jats:sec>Key Results<\/jats:title>R10K<\/jats:styled-content> substitution did not change the conserved \u03c9\u2010conotoxin backbone conformations of CVIE<\/jats:styled-content>&F<\/jats:styled-content> nor the \u03c9\u2010conotoxin selectivity for recombinant or native Cav<\/jats:sub><\/jats:styled-content>2.2 channels, although the inhibitory potency of [R10K<\/jats:styled-content>]CVIF<\/jats:styled-content> was better than that of CVIF<\/jats:styled-content>. At \u221280\u2009mV, the R10K<\/jats:styled-content> chemical modification significantly affected \u03c9\u2010conotoxin\u2212channel interaction, resulting in faster onset kinetics than those of CVIE<\/jats:styled-content>&F<\/jats:styled-content>. Heterologous and native Cav<\/jats:sub><\/jats:styled-content>2.2 channels recovered better from [R10K<\/jats:styled-content>]CVIE<\/jats:styled-content>&F<\/jats:styled-content> block than CVIE<\/jats:styled-content>&F<\/jats:styled-content>. In human serum, the \u03c9\u2010conotoxin half\u2010lives were 6\u221210\u2009h. CVIE<\/jats:styled-content>&F<\/jats:styled-content> and [R10K<\/jats:styled-content>]CVIE<\/jats:styled-content>&F<\/jats:styled-content> were more stable than CVID<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>R10K<\/jats:styled-content> substitution in CVIE<\/jats:styled-content>&F<\/jats:styled-content> significantly alters the kinetics of \u03c9\u2010conotoxin action and improves reversibility without diminishing conotoxin potency and specificity for the Cav<\/jats:sub><\/jats:styled-content>2.2 channel and without diminishing the serum stability. These results may help generate \u03c9\u2010conotoxins with optimized kinetic profiles for target binding.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12686","type":"journal-article","created":{"date-parts":[[2014,3,14]],"date-time":"2014-03-14T04:10:45Z","timestamp":1394770245000},"page":"3313-3327","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effects of arginine 10 to lysine substitution on \u03c9\u2010conotoxin CVIE<\/scp> and CVIF<\/scp> block of Cav<\/sub><\/scp>2.2 channels"],"prefix":"10.1111","volume":"171","author":[{"given":"G","family":"Berecki","sequence":"first","affiliation":[{"name":"Health Innovations Research Institute RMIT University Melbourne Vic Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N L","family":"Daly","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland 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