Synaptic responses mediated by LGICs are designated as excitatory or inhibitory, depending on whether their net effect is to make it more or less likely that the postsynaptic neuron will fire an action potential (Kandel et al.
Activation of this G[beta]/[gamma]-GIRK pathway will produce neuronal inhibition, although on a slower timescale than that produced by inhibitory LGICs. In general, the responses produced by GPCRs are slower in onset and longer lasting than those produced by LGICs because several molecular steps are required to get from the receptor protein to the final effector (in contrast to the direct intraprotein signaling within LGICs).
The fast synaptic excitation produced by glutamate involves the activation of three major subtypes of LGICs, termed the AMPA ([alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (3)-, kainate-, and NMDA (N-methyl-D-aspartic acid) (4)-type receptors based on the synthetic agonists that best activate each receptor (Kandel et al.
When glutamate binds to the NMDA receptor, activation of the intrinsic ion pore is favored, as is the case for AMPA receptors and other LGICs. However, at membrane potentials near the resting potential (e.g., -60 to -70 mV), the ion pore of the NMDA receptor is occluded by magnesium ions (Kandel et al.
Our focus in this research proposal is a group of neurotransmitter receptors that act as LGICs that are known to be effective targets for existing insecticides.
We will build on our recent research that has resulted in the identification of novel binding sites on mammalian LGICs. Our aim will be to develop compounds that interact with similar sites on insect LGICs.