Electrophysiology and Pharmacology of Excitable Membranes  

 

Understanding the molecular events that control excitation in cardiac muscle and the mechanisms by which excitation is modified by drugs is the goal of this laboratory.

 

Experimental models include:

 

• The isolated cardiac myocyte
•  The frog oocyte
• Mammalian cells expressing mRNA transcripts of wild-type and mutant channels
• Embryonic stem cells that express mutant ion channels

 

Experimental techniques include:

 

• DNA and RNA manipulation
• Whole cell voltage clamping
• Exracellular patch clamping

 

A current focus of the laboratory is the voltage gated sodium channel. The problems under study include:

 

• The mechanisms of blockade of channels by antiarrhythmic drugs and neurotransmitters
•  The relationship between channel structure and antiarrhythmic drug binding
•  The development of models to describe the interaction of antiarrhythmic drugs with membrane channels
• Influence of Na-channel mutations on channel gating. These studies include mutations associated with the long QT syndrome
•  The development of in vitro and in vivo models of LQTS and Brugada syndromes

 

These studies should provide a clearer understanding of the cellular basis of cardiac arrhythmias and the mechanisms by which they are terminated by drug. Selected Publications

1. Chandra R, Starmer CF, Grant, AO. Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am J Physiol 274:H643, 1998.

    

2.  

   Chandra R, Chauhan VS, Starmer CF, Grant AO. ß-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+/Na+ selectivity. Cardiovasc Res 42:490, 1999.

    

3.  

   Chauhan VS, Tuvia S, Buhusi M, Bennett V, Grant AO. Abnormal cardiac Na channel properties and QT-heart rate adaptation in neonatal ankyrinB knockout mice. Circ Res 86:441, 2000.

    

4.  

   Grant AO, Chandra R, Keller C, Carboni M, Starmer CF. Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells. Biophysical J 79:3019, 2000.

    

5.  

   Grant AO, Carboni M, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori S. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 110: 1201, 2002.