Long-Term Potentiation and Depression in Synapses

Long-Term Potentiation (LTP) and Phosphorylation

• Repeated synapse use increases transmitter release (LTP), a basis for learning and memory.
• Multiple stimuli can decrease release (LTD), also part of learning and memory.
• Protein phosphorylation is crucial for both LTP and LTD, modifying synaptic strength.

Protein Phosphorylation and Vesicle Release

• Vesicle release proteins are phosphorylated by PKA, a cAMP-stimulated enzyme.
• Adenylyl cyclase, stimulated by Gs proteins and inhibited by Gi proteins, produces cAMP.
• Active PKA quickens SNARE complex formation, increasing synaptic vesicle availability and strengthening responses.
• PKA increases the pool of synaptic vesicles at the active zone.

Long-Term Depression (LTD) and Potassium Channels

• LTD involves potassium channel opening, stabilizing membrane potential at a more negative level.
• PKA increases potassium permeability via inward rectifier channel activity and reduced action potential bursts, also affecting ATP-sensitive potassium channels.

Phosphorylation and RAS Superfamily

• RAS superfamily (Ras, Rab, Rho, Ran, Arf) are activated when GDP is replaced by GTP.
• GTP alters RAS conformation for downstream target binding and activation of kinase activity.
• RAS proteins have inherent GTPase activity, hydrolyzing GTP to GDP and returning to inactive states.
• The duration of GTP-bound RAS is affected by GTPase acceleration, typically by GAPs (GTPase activating proteins).
• GEFs (guanine nucleotide exchange factors) remove tightly bound GDP, allowing GTP substitution.
• GEFs are indirectly produced from second messengers (e.g., cAMP, calcium) or directly by growth factor receptors.
• GDIs (guanosine nucleotide dissociation inhibitors) stabilize inactive Rho-type kinase forms by preventing GEF action.

GTPase Regulation

• GTPase activity is sped up by GAPs (GTPase activating proteins).
• GEFs (guanine nucleotide exchange factors) remove tightly bound GDP, allowing GTP substitution.
• GEFs are indirectly produced from second messengers (e.g., cAMP, calcium) or directly by growth factor receptors.
• GDIs (guanosine nucleotide dissociation inhibitors) stabilize inactive Rho-type kinase forms by preventing GEF action.

Small G Proteins and LTP

• Small G proteins, like Epac (GEF for Rap), are directly activated by cAMP and increase synaptic current amplitude.
• RAB3A, binding to synaptic vesicle membranes, is regulated by GRAB (GEF).