My lab studies the mechanistic basis, and functional consequences, of ion channels, particularly background inward rectifier and ATP-sensitive potassium channels, that are found throughout the cardiovascular system. Our work integrates studies at multiple levels, from the fundamental molecular basis of channel activity to animal models of pathologies associated with human disease. We are interested in how channels are constructed and function, how they regulate individual smooth and cardiac muscles, and how altered channel function contributes to the pathological consequences of aberrant function in the cardiovascular system. Previously, we discovered that soluble cytoplasmic polyamines cause inward rectification and demonstrated their mechanism and sites of action in Kir channels. We have developed the capability to purify Kir and ATP-sensitive (KATP) channels and to analyze these proteins structurally, biochemically and functionally. This allows us to develop and address exciting new questions and hypotheses regarding the fundamental basis of Kir and KATP channel activity, including the molecular mechanisms by which lipids regulate gating and the dynamic structural changes that accompany gating. KATP channels link metabolism to electrical activity in cardiac and smooth muscle. Our recent findings regarding a causal role of KATP channel mutations in human Cantu Syndrome (CS) reveal multiple pathological consequences of underexcitability, including persistence of fetal circulation, pericardial effusion, lymphedema, decreased vascular compliance and decreased gut motility. Development of unique and novel genetically modified animals, as well as a unique research CS clinic, has allowed us to generate extensive preliminary data that begin to explain such features, and leads us to novel hypotheses which will be explored using multiple cell biological and physiological approaches in animals and humans to reach a full understanding of the nature and role of KATP dependent excitability in regulation of cardiovascular function. These studies will form the background to the testing of relevant pharmacological approaches to CS therapy in animal models and in humans, with the ultimate goal of developing a specific therapy for CS and related pathologies.

Public Health Relevance

Cardiovascular disease (CVD) is a leading cause of both adult and neonatal death in the US. Cardiac and vascular function depends on cardiac and smooth muscle electrical activity. We are using molecular, cellular, animal and human studies to understand the mechanistic basis of cardiovascular pathology resulting from altered electrical activity and to develop new specific therapies to treat such cardiovascular pathologies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL140024-03
Application #
9869031
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Balijepalli, Ravi C
Project Start
2018-01-01
Project End
2024-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Shizhen; Brettmann, Joshua B; Nichols, Colin G (2018) Studying Structural Dynamics of Potassium Channels by Single-Molecule FRET. Methods Mol Biol 1684:163-180
Bohnen, Michael S; Ma, Lijiang; Zhu, Na et al. (2018) Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med 11:e002087
Makepeace, Carol M; Suarez-Pierre, Alejandro; Kanter, Evelyn M et al. (2018) Superior diastolic function with KATP channel opener diazoxide in a novel mouse Langendorff model. J Surg Res 227:186-193
Deng, Zengqin; Paknejad, Navid; Maksaev, Grigory et al. (2018) Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms. Nat Struct Mol Biol 25:252-260
Nichols, Colin G; Lee, Sun-Joo (2018) Polyamines and potassium channels: A 25-year romance. J Biol Chem 293:18779-18788
Huang, Yan; McClenaghan, Conor; Harter, Theresa M et al. (2018) Cardiovascular consequences of KATP overactivity in Cantu syndrome. JCI Insight 3:
Shelton, Elaine L; Singh, Gautam K; Nichols, Colin G (2018) Novel drug targets for ductus arteriosus manipulation: Looking beyond prostaglandins. Semin Perinatol 42:221-227
McClenaghan, Conor; Hanson, Alex; Sala-Rabanal, Monica et al. (2018) Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms. J Biol Chem 293:2041-2052
Qiao, Yun; Lipovsky, Catherine; Hicks, Stephanie et al. (2017) Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice. Circ Res 121:549-563