USE OF PHARMACOLOGICAL AGENTS TO IMPLICATE A ROLE FOR PHOSPHOINOSITIDE HYDROLYSIS PRODUCTS IN MALARIA GAMETE FORMATION

The kinetics of phosphoinositol 4,5 bisphosphate hydrolysis products i n activated Plasmodium falciparum gametocytes suggests a role for inos itol trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG) in the sign al transduction pathway of malaria gametocytes. To investigate further this role, compounds that have an effect on the metabolism and biolog ic functions of these second messengers were tested in an in vitro sys tem. Gentamycin, 2,3 diphosphoglycerate (2,3 DPG) and magnesium ion (M g2+), inhibitors of Ins(1,4,5)P3 5' phosphatase, all stimulated gameto cytes to exflagellate in suspended animation buffer, pH 7.4, at room t emperature. In addition, methylxanthines, caffeine and theobromine, ca lcium ionophore (A-23187), and external calcium also stimulated exflag ellation. In contrast, neomycin. an aminoglycoside that inhibits phosp holipase C activity, and heparin, an antagonist of Ins(1,4,5)P3 bindin g to its receptor, inhibited microgamete formation. Quinine and chloro quine which can inhibit both phospholipase A and C activity also inhib ited gametocyte exflagellation. The consistent manner in which these v arious compounds affect gametocyte activation further implicates phosp hoinositol turnover in the signal transduction pathway of falciparum g ametocytes.