Drosophila InsP₃R mutants and their effects on cellular and systemic physiology

Abstract

A single gene encoding two identified splice variants of the InsP₃R is found in the genome of the fruit fly Drosophila melanogaster. Mutants that perturb InsP₃R function differentially have helped identify systemic processes which require the InsP₃R. These include larval feeding, larval molting, fluid transport in malpighian tubules, flight circuit development, and olfactory adaptation. Genetic tools that provide spatiotemporal control on overexpression or knockdown of InsP₃R in the whole organism have aided in delineating cellular domains that influence these processes. Genetic interaction studies with InsP₃R mutants have helped identify several intracellular signaling components that influence InsP₃R function. Measurement of their Ca²⁺ dynamics have further revealed a complex interplay between InsP₃R-mediated Ca²⁺ release, the endoplasmic reticular Ca²⁺ pump, and components of store-operated Ca²⁺ entry (STIM and Orai). Together these players modulate intracellular Ca²⁺ signals and homeostasis. Changes in cellular Ca²⁺ signals brought about by altering levels of the identified intracellular Ca²⁺ signaling components can be correlated with the extent of changes observed in systemic phenotypes. Furthermore, molecular studies of the Drosophila InsP₃R have shown that key functional properties of the InsP₃R are evolutionarily conserved. Thus, insights gained from Drosophila are likely to be relevant for our understanding of human disorders caused by aberrant InsP₃R-mediated Ca²⁺ signaling.