Abstract: Gram-negative bacteria produce endotoxins in the form of lipopolysaccharides (LPS). The direct effect of LPS itself has not been well studied. Peptidoglycan recognition proteins (PGRPs) are potential receptors for LPS in Drosophila and likely other arthropods whereas in mammals the Toll receptors mediate a response by LPS. In larval Drosophila the myogenic heartbeat is dampened by LPS. The LPS exposure at larval Drosophila glutamatergic neuromuscular junctions (NMJ) depresses the amplitude of evoked and spontaneous release, potentially blocking glutamate receptors on the muscle. In contrast, LPS increases evoked response but not quantal events at the crayfish glutamatergic NMJ. In both mentioned invertebrate NMJs, the muscle transiently hyperpolarizes to exposure of LPS and effects on evoked release are reversible with short exposures to LPS. No effects of LPS on primary sensory neurons of crab or crayfish occur. Evoked responses at the cholinergic frog NMJs were depressed but spontaneous quantal events were not. No hyperpolarization of the muscle was observed for frog or rat skeletal muscle from exposure to LPS. The hippocampus of the rodent displayed a rapid depression in evoked responses but is reversible with short exposures. This was also mimicked for sensory-CNS-motor nerve evoked responses in crayfish and larval Drosophila. The RNAi expression for PGRP-LC and PGRP-LE in Drosophila did not alter the responses to LPS. The same dosage of LPS (500 μg mL–1) from Serratia marcescens was used in all animal models. Thus, the effects of LPS on synaptic function and skeletal/cardiac muscle is species and receptor subtype specific but not transmitter subtype specific.