The regulation of synaptic efficacy is an important mechanism for producing plastic changes in neuronal activity associated with development, learning, and neurological and psychiatric disorders. The modulation of ion channel activity by neurotransmitters has often been proposed to be important in synaptic regulation, although there is little direct evidence to support this. Here we propose to continue studies of the molecular mechanism by which serotonin (5-HT) modulates a specific potassium channel (S channel) in Aplysia sensory neurons and to investigate the role of S channel modulation in facilitation of transmitter release from sensory neuron synaptic terminals. I. Mechanism of S channel modulation. Previously we have shown, using single channel recording, that channel modulation by 5-HT involves a phosphorylation reaction mediated by cyclic AMP dependent protein kinase (cAMP-PK). Here we will extend these findings by studying: 1. The role of membrane protein phosphatases in regulating channel modulation and their possible inhibition by specific proteins. 2. The effects of calcium-calmodulin and calcium-phospholipid dependent protein kinases on S channel activity and the modulation of channel activity by cAMP-PK. 3. Whether or not the S channel itself is the important substrate phosphoprotein by determining the importance of peripheral membrane proteins in modulation. II. Mechanism of presynaptic facilitation. To investigate more directly whether S channel modulation is important in regulating transmitter release by serotonin, we will study 5-HT action in growth cones of Aplysia sensory neurons in culture as these are direct precursors to mature synaptic terminals. We will investigate: 1. Whether or not the S channels are present in growth cones and whether they are modulated by 5-HT via a cAMP-dependent mechanism. 2. The effects of 5-HT and cAMP on other voltage dependent ionic currents. 3. Effects of 5-HT on transmitter release as monitored by membrane capacitance increases associated with transmitter vesicle fusion.