Membrane excitability and secretion from peptidergic nerve terminals.

1. Thin slices of the posterior pituitary can be used as a preparation for the study of biophysical mechanisms underlying neuropeptide secretion. Patch-clamp techniques in this preparation have revealed the properties of ion channels that control the excitability of the nerve terminal membrane and have clarified the relation between Ca2+ and exocytosis. 2. Repetitive electrical activity at high frequencies broadens action potentials to allow more Ca2+ entry and thus enhance exocytosis. Action potential broadening results from the inactivation of a voltage-dependent K+ channel. 3. When repetitive electrical activity is sustained, secretion is depressed. This depression can be attributed in part to action potential failure caused by the opening of a Ca(2+)-activated K+ channel. This channel can be modulated by protein kinases, phosphatases, and G-proteins. 4. The inhibitory neurotransmitter GABA activates a GABAA receptor in the nerve terminal membrane. The gating of the associated Cl- channel depolarizes the membrane slightly to inactivate voltage-gated Na+ channels and block action potential propagation. 5. The response of the nerve terminal GABAA receptor is enhanced by neuroactive steroids and this can potentiate the inhibition of neurosecretion by GABA. The action of neurosteroids at this site could play a role in changes in neuropeptide secretion associated with reproductive transitions. 6. Ca2+ channels in the nerve terminal membrane are inactivated by sustained depolarization and by trains of brief pulses. Ca2+ entry promotes Ca2+ channel inactivation during trains by inhibiting the recovery of Ca2+ channels from inactivation. The inactivation of Ca2+ channels can play a role in defining the optimal frequency and train duration for evoking neuropeptide secretion. 7. Measurements of membrane capacitance in peptidergic nerve terminals have revealed rapid exocytosis and endocytosis evoked by Ca2+ entry through voltage-gated Ca2+ channels. Exocytosis is too rapid to account for the delays in neuropeptide secretion evoked by trains of action potentials. Endocytosis sets in rapidly after exocytosis with a time course comparable to that of the rapid endocytosis observed in nerve terminals at rapid synapses. Our results support the finding in rapid synaptic nerve terminals that endocytosis is inhibited by intracellular Ca2+. Multiple pools of vesicles were revealed, and these pools may reflect different stages in the mobilization and release of neuropeptide.