Neural Communication: Synaptic Transmission and cAMP Signaling
Synaptic Transmission: The Release Mechanism
The action potential signal arrives at the axon terminal (the bouton). The local depolarization causes voltage-gated Ca²⁺ channels to open. Calcium (Ca²⁺) enters the presynaptic cell because its concentration is greater outside the cell than inside.
The influx of Ca²⁺ triggers the release of neurotransmitters through the following steps:
- Ca²⁺ binds with calmodulin, causing vesicles filled with neurotransmitter to migrate toward the presynaptic membrane.
- The vesicle merges with the presynaptic membrane.
- The presynaptic membrane and vesicle now form a continuous membrane, releasing the neurotransmitter into the synaptic cleft. This process is called exocytosis.
The neurotransmitter diffuses through the synaptic cleft and binds with receptor channels located in both presynaptic and postsynaptic membranes. These receptor channels are chemically gated. The time period from neurotransmitter release to receptor channel binding is less than a millionth of a second.
Synaptic Plasticity: Modulating Efficacy
The efficacy of transmission at a synapse is not fixed; it can vary significantly based on patterns of ongoing activity. These changes in synaptic efficacy are closely linked to the accumulation and subsequent extrusion of calcium (Ca²⁺) in the presynaptic cytoplasm during activity.
Short-Term Synaptic Changes
Short trains of presynaptic action potentials produce transient changes in transmitter release:
- Facilitation: An increase in transmitter release from the presynaptic terminal that persists for several hundred milliseconds.
- Depression: A reduction in release lasting for seconds, or a combination of both facilitation and depression.
- Augmentation: An intermediate phase of enhancement that decays with a time course similar to synaptic depression.
More prolonged trains of presynaptic action potentials produce Post-Tetanic Potentiation (PTP), an increase in transmitter release that can last for several minutes.
Long-Term Synaptic Changes (LTP and LTD)
At many synapses, repetitive activity can produce changes in efficacy that last for days, known as Long-Term Potentiation (LTP) and Long-Term Depression (LTD).
- Long-Term Potentiation (LTP): Mediated by an increase in Ca²⁺ in the postsynaptic cell. This influx sets in motion a series of second messenger systems that recruit additional receptors into the postsynaptic membrane and, in addition, increase receptor sensitivity.
- Long-Term Depression (LTD): Associated with smaller increases in postsynaptic Ca²⁺ concentrations. LTD is accompanied by a reduction in the number and sensitivity of postsynaptic receptors.
The Role of Cyclic AMP (cAMP) as a Second Messenger
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a multitude of cellular responses.
cAMP Formation and Effectors
cAMP formation usually depends upon the activation of G-protein-coupled receptors (GPCRs). These receptors use heterotrimeric G proteins to activate the amplifier, adenylyl cyclase (AC).
AC is a large family of isoforms that differ considerably in both their cellular distribution and activation mechanisms.
There are a number of cAMP signaling effectors, including:
- Protein Kinase A (PKA)
- Exchange Proteins Activated by cAMP (EPACs), which activate the small GTP-binding protein Rap1.
- Cyclic Nucleotide-Gated Channels (CNGCs).
These various effectors are responsible for carrying out cAMP signaling functions, which include the control of metabolism, gene transcription, and ion channel activity. In many cases, these functions are modulatory, meaning cAMP often acts to adjust the activity of other signaling pathways, thus playing a central role in cellular cross-talk.