Long-??chainpolyunsaturatedomega-??3fattyacids,suchasdocosahexaenoicacid(DHA)witha22-??carbon chain,arefoundabundantlyinoilyfishincludinganchovy,herring,mackerel,andsalmon.Theseomega-??3 fattyacidsarewidelythoughttohavemultiplehealth-??promotingeffects.EvidencesuggeststhatDHA decreasesbloodpressure,especiallyinhypertensivepatients.Wehypothesizethatthehypotensiveaction ofDHAismediatedbyitsstimulatoryeffectonlarge-??conductancecalciumandvoltage-??gatedpotassium (Slo1BK)channelsimportantinbloodpressureregulation.Theresearchprogramproposedherewill providemolecularandatomicbasisofthehypotensiveactionofDHAinvolvingSlo1BKchannelsusing biophysical,biochemical,andwhole-??animalmethods.Wepostulatethatahydrogenbondbetweena tyrosineresidueintheS6segmentofthechannelandthecarboxylategroupiscriticalindestabilizingthe closedconformationoftheionconductiongateandthisinteractionunderliesthewhole-??animal hypertensiveaction.Usingthephysicochemicalprincipleselucidated,wewillrationallydesign,synthesize andtestfatty-??acidactivatorsofSlo1BKchannels.Theanticipatedoutcomeoftheresearchprogramhas potentialtoexplainbloodpressureregulationofwholeanimalsbasedonthehydrogenbondsformed betweenspecifictyrosineresiduesoftheSlo1BKchannelandDHAandprovideasolidmechanistic foundationfordiscoveryanddevelopmentofpharmaceuticalsandnutraceuticalsforbloodpressure management.
Omega-??3fattyacidsarefoundathighlevelsinoilyfishsuchasanchovy,herring,mackerel,andsalmon andthusthesefattyacidsareoftenreferredtoas?fishoils?.Wewillelucidatephysicalandchemical mechanismsbywhichomega-??3fattyacidsregulateionchannelproteinsinvolvedincellexcitationatan atomiclevelandcomparehowwholeanimalsrespondtoomega-??3fattyacidsintheirfood.Theanticipated outcomeoftheresearchprogramwilladvanceourunderstandingofthehealthprotectiverolesoffishoils.
| Gessner, Guido; Sahoo, Nirakar; Swain, Sandip M et al. (2017) CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2). Eur J Pharmacol 815:33-41 |
