This grant project investigates the properties of a non- selective ion channel (channels are functionally important proteins located in the cell membrane). The non-selective channel plays an important part in slow excitation of brain cells induced by brain chemicals. The overall summation of the excitatory state of each of the brain cells in each specialized nucleus (region) of the brain determines the tone of the brain. In spite of its widespread nature and its functional importance, the non-selective channel has long been ignored, and little is known about its properties. To investigate this channel in brain neurons has been difficult because of the lack of a suitable cell type. Recently, the laboratory of the principal investigator has found that cultured neurons from the ventral tegmental area (a brain region playing an important part in the pathogenesis of schizophrenia) are an excellent cell type for this purpose, since this channel is consistently activated by four excitayory chemicals: (1) neurotensin, (2) neurokinin B, (3) metabotropic glutamate agonist, (4) and muscarine Thus, it is now feasible to conduct a systematic investigation of this channel. The specific projects examine: (1) whether each one of these brain chemicals acts on its own receptor, (2) the permeability of the channel to various ions, (3) the signal transduction mechanism (details of the events leading to a slow excitation of the neuron). (4) the pharmacology of this channel, and (5) the single channel properties of this channel. Preliminary results suggest that this non- selective channel has unusual characteristics: (1) It is different from a Ca-activated non-specific cation channel. (2) The channel activiation is independent of G proteins (an important protein for many types of signal transduction). (3) Yet, it does not seem to be a ligand- gated channel (usual channel for very quick excitation), since the latency of activation is very long.
