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AK Grover,Professor Dept. Medicine
BSc Hons and MSc (Botany) Delhi Univ., PhD (Microbial Biochemistry) Calgary Univ.
Associate Member: Dept. of  Biology, Member: Smooth Muscle Research Program,IDRP, MOBIX
Project Leader: Oxidative Stress Consortium,Career Investigator Award (until Dec. 31, 2004) (Heart & Stroke Foundation of Ontario)
HSC 4N41, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
Tel: 905-525-9140 ext. 22238, FAX: 905-522-3114, groverak@mcmaster.ca
Education:  Fundamental Concepts of Pharmacology ( Biology 3AA3):  includes student assessments and comments  + Announcements

Research:

 

Coronary artery, calcium pumps, NCX and oxidative stress:  Coronary artery smooth muscle contraction makes the arteries narrower and relaxation makes them wider.  This helps regulate blood supply to the heart.  Calcium ions are brought into cell cytoplasm by various channels and removed from it by three main pathways: plasma membrane calcium pumps (PMCA), sarco/endoplasmic reticulum calcium  pumps (SERCA) and sodium-calcium-exchanges (NCX).  Our lab has works on these mechanisms with a current focus on NCX.  NCX extrudes calcium ions from cells under normal electrochemical gradients of sodium and calcium.  Typically high calcium concentrations in the artery muscle cells cause them to contract. Arteries also contain an inner lining of endothelial cells.  Increasing calcium in endothelial cells causes them to produce substances such as nitric oxude that can relax the smooth muscle cells.  Thus high calcium in  smooth muscle and endothelial cells have opposite effects. Therefore, our first goal is to understand the effects of this balance on the two cell types.   We are also exploring the hypothesis that NCX and SERCA may be linked.

        Reactive oxygen is like fire - our body makes variousreactive oxygen  species to get energy and as signalling molecules.  However, fire out of control is no good.  Too much reactive oxygen can be formed in heart failure.  This may cause the heart to deteriorate faster if coronary arteries cannot supply blood to it properly. We have examined the effects of reactive oxygen species on PMCA and, SERCA in coronary artery and we will now focus on the effects of reactive oxygen on NCX.

Caloxins - a novel class of compounds: For a long time, this was our dream project. Inhibitors of PMCA are needed to understand the exact role of  the pumps in calcium ion homeostasis.  We dreamed of  and searched for caloxins as inhibitors of the PMCA. We have now discovered several prototype caloxins.   This discovery is the dream come true.

        PMCA genes 1, 2, 3 or 4 encode different PMCA isoforms that are expressed in a tissue dependent manner. In coronary artery, the endothelium expresses mainly PMCA1 and the smooth muscle expresses PMCA4 and PMCA1. Thus, caloxins selective for individual PMCA isoforms will help discern the roles of PMCA in blood vessel function.  PMCA isoforms differ in the sequence of their extracellular domain 1.  We invented a prototype PMCA4 selective caloxin (1c2) using this as a target. We propose  to improve it, obtain PMCA1 selective caloxins, and use caloxins to study coronary artery function.  We will discern the role of PMCA in coronary artery tone. The isoform  selective caloxins will be a milestone for solving complex problems in PMCA biology, e.g., distinction between the roles of caveolar vs. non-caveolar PMCA (or PMCA in lipid rafts vs. outside the lipid rafts in neurons). Caloxins  may also become useful in understanding the role of PMCA isoforms in hypertension, heart failure and stroke.

         Approaches and methods: It uses concepts and methods in molecular biology (e.g., phage display screening, creating libraries, RT-PCR, cloning), cell biology (e.g., confocal microscopy, monitoring intracellular ion concentrations using fluorescence probes), biochemistry (e.g., Western blots,  immunoprecipitation,  membrane and protein isolation, enzyme activity measurements, ion transport assays, determining concentrations of various metabolites), physiology and pharmacology (monitoring the effects of different drugs on arterial contractility using organ baths).

Manuscripts Accepted D

Davis, K., Samson, S., Kiss, L., Fulop, F., Grover, A.K. (2008)  Functional linkageof Na-Ca-exchanger to sarco/endoplasmic reticulum Ca pump in coronary artery: comparison of smooth muscle and endothelial cells J. Cell. Mol. Med.

Recent Publications: