In invertebrates, insulin-like peptides have been convincingly localized to neurons, and some have been shown to fulfill classical criteria expected of neurotransmitters as well as their well-known activities as growth factors and metabolic hormones. Examination of the electrophysiological effects of the mammalian hormone on molluscan neurons reveals that insulin causes hyperpolarization of certain identified neurons of the marine mollusc, Aplysia. cDNA cloning, immunoblot analyses and immunocytochemistry provide evidence for the presence of insulin-like tyrosine kinase receptor(s) in bag cells, neuropil, and in as yet unidentified neurons in central Aplysia ganglia. Immunocytochemistry with both vertebrate and invertebrate anti- insulin antibodies shows staining of neurons, neuropil and gut, indicating the existence of insulin-like Aplysia peptides. Three questions about the presumptive actions of insulin and insulin-like peptides as neurotransmitters that modulate synaptic action will be approached in the nervous system of Aplysia: (1) What is the structure of the endogenous molluscan neuropeptides whose action is mimicked by vertebrate insulin? (2) Are tyrosine kinase signal transduction mechanisms used by these insulin-like peptides to modulate synaptic transmission? and (3) What are the neurophysiological and behavioral effects of insulin-like peptides? The ability of invertebrate neurons to synthesize and release insulins suggests that peptides of the insulin superfamily act not only as hormones to control growth and metabolism, but also as modulatory neurotransmitters. Neuropeptides that function as hormones or growth factors to initiate longer-term metabolic, behavioral or developmental processes also can produce short-term electrophysiological effects on neurons. Specifically, our working hypothesis is that insulin-like peptides serve to integrate behaviors, suppressing activities that are inappropriate when the animal feeds: inking, a defensive behavior, through actions on cell L14, the inking motor neuron, and egg-laying, a reproductive behavior, through actions on the bag cells. The specific experimental advantages Aplysia offer is the opportunity (1) to show that insulin-like peptide(s) act as neuropeptides (as well as hormones); (2) to identify specific neural circuits that mediate or integrate specific behaviors in addition (3) to identify the particular biochemical second messenger pathway(s) and neurophysiological mechanisms within those neurons that underlie the behavior or behavioral changes. To our knowledge, this would be the first opportunity to study a neuropeptide whose actions may be mediated through a tyrosine kinase signal transduction pathway.
| Jonas, E A; Knox, R J; Kaczmarek, L K et al. (1996) Insulin receptor in Aplysia neurons: characterization, molecular cloning, and modulation of ion currents. J Neurosci 16:1645-58 |
