Pharmacogenetic approaches in altering heart rate in Drosophila larvae

Abstract

Fruit fly, Drosophila melanogaster, is a good model organism to study the underlying ionic mechanism of heart rate (HR) regulation. It is already known that many neuromodulators (serotonin, dopamine, octopamine, acetylcholine) change the HR in larvae. We used genetic and pharmacological approaches to investigate the extent to which cAMP‐PKA signaling mediates the effects of serotonin (5‐HT) and dopamine (DA) on larval HR. One approach involved the use of transgenic flies that express designer receptors exclusively activated by designer drugs (DREADDs). These engineered G‐protein coupled receptors helped to demonstrate that the effect of 5‐HT, which increases HR, could be overridden by the action of Gái which in turn inhibits adenylyl cyclase (AC). Moreover, activation of AC by forskolin increased HR. However, application of dbcAMP (cAMP analogue, PKA activator) and SQ, 22,536 and ddadenosine (AC inhibitors) did not have a substantial effect on the HR. DA activates parallel signaling cascades in cardiac cells with the end result of increased HR. SKF38393 (a vertebrate D1 agonist) and quinpirole (a vertebrate D2 agonist) increase HR to various degrees. SCH23390 and spiperone (D1 and D2 antagonists) each inhibit the stimulatory effect of DA. And SQ22536 inhibits the effect of DA. Together these results indicate that serotonin and dopamine regulate fruit fly HR through canonical GPCR pathways.