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Roles of Ca2+, hyperpolarization and cyclic nucleotide activated channel activation, and actin in temporal synaptic tagging


At crayfish neuromuscular junctions, cAMP increases transmitter released by action potentials by activating two effectors, hyperpolarization and cyclic nucleotide-activated channels (HCNCs) and a separate target that has been tentatively identified as exchange protein activated by cAMP ( Epac). Intense electrical activity in the motor neuron induces a long-term facilitation (LTF) of transmitter release in which hyperpolarization from an electrogenic Na+-K+ exchanger activates HCNCs. The coupling of HCNCs to transmission involves actin. After LTF induction, cAMP further increases transmission in an HCNC-independent manner, activating the second target. This relaxation of the requirement for HCNC activation to enhance release is called temporal synaptic tagging. Tagging lasts at least 1 d but develops only in the 10 min period after electrical activity. The HCNCs are activated by the post-tetanic hyperpolarization occurring during this time. Both synaptic tagging and LTF induction depend on presynaptic Ca2+ accumulation during activity; both are blocked by EGTA-AM, and LTF is also prevented by stimulation in a low-[Ca2+] medium. Actin depolymerizers prevent induction of LTF and tagging, with little effect on HCNCs, whose sensitivity to cAMP and HCNC blockers is unaffected by tagging. Enhancement of actin polymerization can rescue tagging from HCNC block, suggesting that actin acts at a step after HCNC activation. These and other recent results suggest a model in which HCNC activation, followed by a process involving actin polymerization, acts cooperatively with [Ca2+] to induce tagging, after which only Epac activation is required for cAMP to further enhance transmission.

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