MOLECULAR BIOLOGY OF NEURAL FUNCTION

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The following summary describes three projects examining the roles of kinesin light chains (KLC), nsec-1 and acidic calponin (AC) play in neural function. The fourth examines the downstream targets of signal transduction enzymes induced at the neuromuscular junction by the myomodulin and buccalin peptide families from the sea hare Aplysia californica. KLCs and nsec-1 are proteins that effect synaptic vesicle (SV) transport. We have identified at least nine isoforms of KLC from squid optic lobe and are currently focussing on determining the function of the C-terminal tail domains. We are also pursuing this question in vivo by genetic knockout analysis using the technique of homologous recombination. We have previously identified nsec-1 as a regulator of neuronal Cdk5 kinase activity towards neurofilament proteins. Several questions remain regarding how mutation of nsec-1 affects SV trafficking. We are currently endeavoring to identify the remaining components of the nsec-1/Cdk5 complex and determine their respective functions as they relate to Cdk5 activity. AC is a nonsmooth muscle isoform of basic calponin that we have shown localizes to the developing growth cones of neurons. AC levels diminish as neurons differentiate and a number of regulatory domains in the unique C-terminal tail domain including a PEST domain, an isoprenylation site, a P-loop element and a tyrosine phosphorylation site all suggest mechanisms for regulating protein second messenger-induced translocation and protein turnover. Current research is directed toward addressing how these domains relate to protein function. We have also participated in identifying twitchin, a 750 kDa muscle protein, as a primary target of PK-A phosphorylation following ARC muscle stimulation with the neuro peptide myomodulin in Aplysia californica. Further work is directed towards elucidating receptors and other downstream targets of the signal transduction cascades in response to stimulation by the neuropeptides buccalin and myomodulin.