Module 2 | Source: A Brain-Mind Odyssey, UC Berkeley, Ch. 6
Tags: synapse, electrical synapse, chemical synapse, gap junction, connexon, neurotransmitter, receptor, ionotropic, metabotropic, GPCR, G-protein, EPSP, IPSP, glutamate, GABA, acetylcholine, reuptake, synaptic cleft, second messenger, cAMP
Neurons communicate at synapses using either direct electrical connections (gap junctions) or chemical signalling via neurotransmitters. Chemical synapses offer far more regulatory flexibility: neurotransmitter released from the presynaptic terminal crosses the synaptic cleft, binds to receptors (ionotropic for fast effects, metabotropic/GPCR for slower and more varied effects), and the resulting EPSPs and IPSPs are summed at the axon hillock to determine whether the postsynaptic neuron fires.
Electrical synapse (gap junction)
A direct physical connection between two neurons, built from clusters of channel proteins (connexons) embedded in both cell membranes. Ions pass straight through, producing very fast signal transmission.
Connexon
A single channel in a gap junction, formed from six connexin protein subunits arranged in a doughnut shape with a central pore.
Connexins
The individual protein subunits that assemble to form a connexon.
Chemical synapse
A synapse where a physical gap (the synaptic cleft) separates the pre- and postsynaptic cells. Signal transmission requires release of neurotransmitter molecules. More complex and more regulable than electrical synapses.
Synaptic cleft
The narrow gap (approximately 20 nm) between the presynaptic axon terminal and the postsynaptic cell, filled with water and ions.
Neurotransmitter
A signalling molecule stored in synaptic vesicles in the axon terminal and released into the synaptic cleft upon arrival of an action potential.
Synaptic vesicle
A small membrane-bound sphere inside the axon terminal that stores neurotransmitter molecules.
SNARE complex
The protein machinery that facilitates fusion of synaptic vesicles with the presynaptic membrane, enabling neurotransmitter release. Activated by Ca++ influx.
Reuptake transporter
A membrane protein in the presynaptic terminal that moves neurotransmitter back into the cell from the synaptic cleft, terminating the signal for most neurotransmitters.
Acetylcholinesterase
The enzyme in the synaptic cleft that breaks acetylcholine into acetate and choline, inactivating it. This is the primary clearance mechanism for ACh (rather than reuptake).
Glutamate
The most abundant and primary excitatory neurotransmitter in the human brain. Also one of the 20 standard amino acids.
GABA (gamma-aminobutyric acid)
The major inhibitory neurotransmitter in the human brain. Synthesised from glutamic acid by the enzyme glutamic acid decarboxylase.
Glutamic acid decarboxylase
The enzyme that converts glutamic acid (glutamate) into GABA.
Ionotropic receptor (ligand-gated channel receptor)
A receptor protein that spans the membrane and contains an ion channel (pore). When the appropriate neurotransmitter binds, the channel opens directly. Fast-acting.
EPSP (excitatory postsynaptic potential)
A small depolarization of the postsynaptic membrane, most commonly produced by ionotropic glutamate receptors allowing Na+ or Ca++ influx.
IPSP (inhibitory postsynaptic potential)
A small hyperpolarization of the postsynaptic membrane, most commonly produced by ionotropic GABA receptors allowing Cl– influx.
Metabotropic receptor (GPCR, G-protein-coupled receptor)
A receptor that does not contain an ion channel itself. Instead, neurotransmitter binding activates an intracellular G-protein, triggering a cascade of slower, more varied, and longer-lasting effects.
G-protein
An intracellular protein activated when a neurotransmitter binds a metabotropic receptor. Activation involves exchange of GDP for GTP and splitting into subunit proteins that go on to affect effector enzymes.
Effector enzyme
Intracellular enzyme targeted by activated G-protein subunits (e.g. adenylate cyclase). Produces downstream signalling molecules.
Second messengers (intracellular messengers)
Small molecules generated inside the cell in response to metabotropic receptor activation: cAMP, cGMP, IP3, and DAG. The neurotransmitter itself is considered the "first messenger."
Protein kinase
An enzyme activated by second messengers (e.g. cAMP) that catalyses attachment of phosphate groups to other proteins, altering their function.
Electrical synapses (gap junctions) allow ions to pass directly between cells via connexon channels. Transmission is very fast, faster than chemical synapses.
Chemical synapses separate cells by a cleft. They are slower but offer much richer regulation: signal strength can be modulated, feedback loops are possible, and different target cells can respond differently.
An action potential propagates to the axon terminal.
At the terminal, there are no voltage-gated Na+/K+ channels. Instead, voltage-gated Ca++ channels open.
Ca++ flows in and binds to SNARE complex proteins.
Synaptic vesicles fuse with the presynaptic membrane and release neurotransmitter into the cleft.
Neurotransmitter molecules diffuse across the cleft and bind to receptor proteins on the postsynaptic membrane (like a key in a lock).
Receptor activation passes a signal into the postsynaptic cell.
Presynaptic receptors can also bind released neurotransmitter, providing feedback regulation.
Most neurotransmitters are removed by reuptake transporters in the presynaptic membrane, which pull the molecule back into the axon terminal.
Acetylcholine is the exception: it is broken down in the cleft by acetylcholinesterase into acetate and choline.
Ionotropic receptors: neurotransmitter binds, channel opens, ions flow, membrane potential changes rapidly. One action, very fast.
Metabotropic receptors (GPCRs): neurotransmitter binds, G-protein activates (GDP swapped for GTP), G-protein splits into subunits, subunits interact with effector enzymes (e.g. adenylate cyclase), second messengers (cAMP) are produced, protein kinases are activated, which phosphorylate downstream targets including ion channels and transcription factors. Multiple steps, slower onset, more varied and prolonged effects.
EPSPs are produced when ionotropic receptors allow Na+ or Ca++ into the cell (depolarization).
IPSPs are produced when ionotropic receptors allow Cl– in or K+ out (hyperpolarization).
A single neuron receives input from dozens to thousands of other neurons, some excitatory, some inhibitory.
All EPSPs and IPSPs are summed at the axon hillock. If the net voltage reaches threshold (approximately –50 mV), an action potential fires.
Temporal summation: repeated signals from the same input neuron in quick succession.
Spatial summation: signals arriving from multiple input neurons at roughly the same time.
Neurotransmitter binds the extracellular face of the receptor.
Receptor changes shape, exposing an intracellular binding site for G-protein.
G-protein binds, exchanges GDP for GTP, and splits into subunit proteins.
Subunits travel along the inner membrane surface and may activate adenylate cyclase.
Adenylate cyclase catalyses formation of cAMP (cyclic AMP).
cAMP activates protein kinases, which phosphorylate substrate proteins.
Targets include ion channels (opening or closing them) and transcription factors (turning genes on or off).
Synaptic cleft width: ~20 nm
Ionotropic receptor subunit structure: typically 4–5 protein subunits arranged around a central pore
GPCR cascade: Neurotransmitter → receptor → G-protein (GDP→GTP) → effector enzyme (adenylate cyclase) → second messenger (cAMP) → protein kinase → phosphorylation of target proteins
Summation rule: ΣEPSPs + ΣIPSPs at axon hillock ≥ –50 mV → action potential fires
⚠️ Be able to contrast electrical and chemical synapses: speed, complexity, and regulatory potential.
⚠️ The Ca++ entry step at the axon terminal is the critical link between the arriving action potential and neurotransmitter release. Ca++ channels here are voltage-gated, not Na+ or K+ channels.
⚠️ Glutamate = main excitatory neurotransmitter. GABA = main inhibitory neurotransmitter. This pairing is tested constantly.
⚠️ Know that GABA is synthesised from glutamate by glutamic acid decarboxylase.
⚠️ Ionotropic = fast, direct channel opening. Metabotropic (GPCR) = slow, multi-step cascade, varied effects. Expect comparison questions.
⚠️ Acetylcholine clearance differs from other neurotransmitters: enzymatic breakdown (acetylcholinesterase) rather than reuptake.
⚠️ Spatial vs. temporal summation: both are ways that subthreshold inputs combine to reach threshold.
Q: What is the key structural difference between an electrical synapse and a chemical synapse?
A: An electrical synapse has direct physical channels (connexons/gap junctions) connecting the cytoplasm of two cells. A chemical synapse has a physical gap (synaptic cleft, ~20 nm) that neurotransmitter must cross.
Q: What ion triggers neurotransmitter release at the axon terminal, and how does it get in?
A: Calcium (Ca++). It enters through voltage-gated calcium channels that open when the action potential depolarises the axon terminal membrane.
Q: How does GABA produce an inhibitory effect on the postsynaptic neuron?
A: GABA binds to ionotropic GABA receptors, which open Cl– channels. Cl– flows into the cell from outside, making the interior more negative (hyperpolarization), producing an IPSP.
Q: What distinguishes an ionotropic receptor from a metabotropic receptor?
A: An ionotropic receptor contains a built-in ion channel that opens directly upon neurotransmitter binding, producing a fast response. A metabotropic receptor has no channel of its own; it activates a G-protein signalling cascade that produces slower, more varied, and longer-lasting effects inside the cell.
Q: What are second messengers, and name two examples?
A: Second messengers are intracellular signalling molecules produced in response to metabotropic receptor activation. The neurotransmitter is the "first messenger." Examples include cAMP (cyclic AMP) and IP3 (inositol trisphosphate). Others include cGMP and DAG.
Q: How does the postsynaptic neuron "decide" whether to fire an action potential?
A: It sums all incoming EPSPs and IPSPs (via spatial and temporal summation). If the net depolarization at the axon hillock reaches the threshold of about –50 mV, voltage-gated Na+ channels open and an action potential is triggered.
synapse, electrical synapse, gap junction, connexon, connexin, chemical synapse, synaptic cleft, neurotransmitter, synaptic vesicle, SNARE complex, exocytosis, reuptake transporter, acetylcholinesterase, glutamate, GABA, gamma-aminobutyric acid, glutamic acid decarboxylase, ionotropic receptor, ligand-gated channel, metabotropic receptor, GPCR, G-protein, adenylate cyclase, cAMP, second messenger, protein kinase, phosphorylation, EPSP, IPSP, excitatory postsynaptic potential, inhibitory postsynaptic potential, spatial summation, temporal summation, Otto Loewi, Vagusstoff, acetylcholine