Although it generally is appreciated that Ca channels play crucial roles in the shaping of action potentials and firing patterns, as well as in the control of transmitter release at nerve terminals, the study of these roles has been limited by the availability of selective tools for blocking Ca channels. The recent isolation of omega-Aga-IVA (from spider venom) constitutes a significant advance since this toxin may be used to target a unique population of Ca channels whose roles were difficult to isolate previously. Funds are requested to continue these studies in three different ways: 1) patch-clamp recordings from tissue slices or freshly isolated neurons to investigate whether the toxin blocks more than one population of Ca channels (as suggested recently by R. W. Tsien and collaborators); 2) photometric studies of presynaptic Ca transients to determine the regulation of synaptic strength by transmitters that affect presynaptic Ca channels differentially; and 3) patch-clamp recordings of Purkinje cells in combination with photometric measurements of Ca to study the link between P-type Ca channels and internal Ca release, and their contribution to the processing of synaptic inputs. Since Ca channels sensitive to omega-Aga-IVA are ubiquitous in the CNS, there is no question that these studies will provide greater insight into the many cellular functions controlled by calcium (e.g. promotion of neuronal growth, regulation of genes and enzymes, etc.) as well as into the pathological situations that arise when Ca homeostatic mechanisms are disrupted, as is thought to occur with epilepsy, excitotoxicity, and neuronal death.
| Sidach, S S; Mintz, I M (2000) Low-affinity blockade of neuronal N-type Ca channels by the spider toxin omega-agatoxin-IVA. J Neurosci 20:7174-82 |
