Abstract
Approaches are sought after to regulate ionotropic and chronotropic properties of the mammalian heart. Electrodes are commonly used for rapidly exciting cardiac tissue and resetting abnormal pacing. With the advent of optogenetics and the use of tissue-specific expression of light-activated channels, cardiac cells cannot only be excited but also inhibited with ion-selective conductance. As a proof of concept for the ability to slow down cardiac pacing, anion-conducting channelrhodopsins (GtACR1/2) and the anion pump halorhodopsin (eNpHR) were expressed in hearts of larval Drosophila and activated by light. Unlike body wall muscles in most animals, the equilibrium potential for Cl− is more positive as compared to the resting membrane potential in larval Drosophila. As a consequence, upon activating the two forms of GtACR1 and 2 with low light intensity the heart rate increased, likely due to depolarization and opening of voltage-gated Ca2+ channels. However, with very intense light activation the heart rate ceases, which may be due to Cl– shunting to the reversal potential for chloride. Activating eNpHR hyperpolarizes body wall and cardiac muscle in larval Drosophila and rapidly decreases heart rate. The decrease in heart rate is related to light intensity. Intense light activation of eNpHR stops the heart from beating, whereas lower intensities slowed the rate. Even with upregulation of the heart rate with serotonin, the pacing of the heart was slowed with light. Thus, regulation of the heart rate in Drosophila can be accomplished by activating anion-conducting channelrhodopsins using light. These approaches are demonstrated in a genetically amenable insect model.
Highlights
Cardiovascular dysfunction is a major health problem in modern societies [1]
The 2nd chromosomal lines (GtACR1attP40 and GtACR2attP40), with the same light exposures performed on the same day and time period, showed similar responses (n = 10; p < 0.05; Figure 2C1,D1)
We demonstrate a proof of concept to control heart rate in Drosophila by manipulating the flow of chloride ions with light
Summary
Cardiovascular dysfunction is a major health problem in modern societies [1]. Some cardiac disorders involve issues in the electrical pacing of the heart [2,3]. Extrinsic electrical regulation of the mammalian heart is accomplished with wires placed, as electrodes, in contact with the heart [4] These electrodes provide stimulating defibrillation to the tissue to either pace or reset the intrinsic electrical activity in the cases of cellular pacemaker failure or in atrial or ventricular fibrillation and tachycardia. Prolonged inhibition of electrical activity is not possible with electrical defibrillation of the tissue for acute cardiac surgery or experimental studies These limitations can potentially be overcome by using optogenetics to regulate the activity of pacing cells in desired directions [10,11,12,13]
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