"Being responsible for my own research project has been a great incentive to step out of my scientific comfort zone and explore areas less familiar to me such as Molecular Biology. These bacteria were transformed to produce a plasmid containing a synthetic piece of double stranded DNA I designed." - Lisi Krainer
Link to PubMed (Opens new window. Close the PubMed window to return to this page.)
The contractile function of the heart is controlled by the electrical activity initiated in the pacemaker sinoatrial node and conducted throughout the heart. An electrical impulse, called an action potential, is generated by specific ion channels that are directly regulated by membrane voltage or ionic blockade. The rapid transmission of this 1/10th of a volt signal is accomplished by gap junctions, a type of intercellular junction which forms a tunnel-like channel. Gap junctions are typically open at rest and, hence, do not require voltage-dependent activation. Little is known about how gap channel proteins, called connexins, conduct electric current and how this current flow is regulated by physiological or pathophysiological (disease) conditions.
By producing site-directed mutations in the two major cardiac gap junction proteins, connexin43 (Cx43) and connexin40 (Cx40), we are examining the molecular basis for the selective electrical conductance and molecular permeability properties of cardiac gap junctions. We hope to make structural inferences about gap junction channel pore structure by observing how endogenous polyamines, small polybasic molecules derived from amino acids such as spermine, block Cx40 and three other connexin gap junctions while having no effect on Cx43 and the majority of other 20 mammalian connexin-specific gap junctions. Intracellular calcium elicits myocardial contraction and, at least under pathophysiological conditions, can shut down gap junction communication. Recently published observations provide new insights as to how this is effected and we are studying how the (patho)physiological regulation of cardiac, lens, and liver gap junctions may be altered by naturally occurring mutations. We are also examining the mechanisms by which human atrial fibrillation mutations in Cx40 or Cx43 alter cardiac gap junction function to produce cardiac arrhythmias or other human diseases.
There is no known clinical therapeutic pharmacology for gap junctions despite their importance to the conduction of the heartbeat for every second of life. We have investigated the mechanism by which the first experimental gap junction agonist, rotigaptide, helps preserve gap junction communication during a heart attack and slow the onset of lethal cardiac arrhythmias. We have also begun investigating what effects novel types of anti-cancer drugs called histone deacetylase (HDAC) inhibitors have on cardiac gap junctions and the action potential they conduct. Preliminary evidence suggests that under-appreciated protein post-translational modifications like acetylation and arginylation modulate the cardiac action potential and its conduction in addition to phosphorylation. These studies involving novel protein post-translational modifications and experimental/clinical drugs are continuing in the laboratory.