Salt and water balance in insects: Molecular mechanisms and potential biomedical targets

A hormone that regulates K⁺ balance in insects has not yet been found.  Apparently, Malpighian tubules autoregulate extracellular K⁺ homeostasis.  Two channels AeKir1 and AeKir2B mediate the entry of K⁺ from the hemolymph into epithelial cells of Malpighian tubules in the yellow fever mosquito Aedes aegypti, and two antiporters (NHA1,2) and one cotransporter (KCC) translocate K⁺ from the cytoplasm to the lumen.  These mediators of transepithelial K⁺ secretion offer unique targets for the control of harmful insects.  For example, the “small molecule” VU590 (discovered in high throughput screens) inhibits AeKir1 (but not AeKir2B) expressed in HEK cells and Xenopus oocytes.  It inhibits the transepithelial secretion of KCl but not NaCl in isolated Malpighian tubules, and injected into the hemolymph, VU590 kills mosquitoes within 24 hours.  Swollen abdomens suggest renal failure at the level of the channel AeKir1 in Malpighian tubules.  These observations invite a paradigm shift in the control of harmful insects.  Disrupting salt and water homeostasis offers two principal advantages: 1) a wide spectrum of molecular targets from antidiuretic and diuretic hormones to epithelial transport mechanisms at the level of membrane proteins, 2) the potential of group- or even species-specific “small molecules” that interfere, for example, in salt and water balance in hematophagous insects but not in phytophagous insects.  In view of the increasing resistance of insects to the neuronal insecticides currently in use, the exploration of “salt and water balance” for new ways of selectively controlling populations of harmful insects is not only timely but also desirable.    

Supported by 1) a grant from the FNIH through the Vector-Based Transmission of Control: Discovery Research (VCTR) Program of the Grand Challenges in Global Health Initiative, and 2) grant 1R01DK082884 awarded to J.S. Denton.