Notes on 12.5: Communication Between Neurons — Graded Potentials and Neurotransmission

Graded Potentials

  • The electrical changes inside a neuron resemble a light switch: a stimulus starts depolarization, but the action potential runs autonomously once threshold is reached.
  • Graded potentials are temporary changes in the membrane voltage and are usually associated with the dendrites.
  • The amount of change depends on the size of the stimulus.
    • Example: testing shower temperature—the amount of membrane potential change increases with hotter water.
  • Graded potentials can be depolarizing or hyperpolarizing (Figure 12.25).
    • Depolarizing potentials: typically due to Na extsuperscript{+} or Ca extsuperscript{2+} entering the cell.
    • Rationale: these ions are at higher concentrations outside the cell and carry positive charge; their inward movement makes the inside less negative.
    • Hyperpolarizing potentials: typically due to K extsuperscript{+} leaving the cell or Cl extsuperscript{−} entering.
    • Rationale: loss of positive charge or gain of negative charge makes the cell more negative inside.
  • Resting membrane potential context:
    • Resting potential is around Vrest ≈ −70 mVV_{rest} \,\approx\, -70\ \text{mV}.
    • Depolarization or hyperpolarization occurs relative to this value.
  • Relationship to action potentials:
    • Graded potentials influence whether an action potential will occur by moving the membrane toward or away from threshold.
    • They are the precursor signals that can summate to reach threshold.

Types of Graded Potentials

  • Generator potential (unipolar sensory neurons):
    • Develop in the dendrites and influence the generation of an action potential in the axon of the same cell.
  • Receptor potential (sensory receptor cells):
    • In taste cells or retinal photoreceptors, graded potentials lead to neurotransmitter release at synapses with sensory neurons.
  • Postsynaptic potential (PSP):
    • Graded potential in the dendrites of a neuron that is receiving synapses from other cells.
    • Can be depolarizing (EPSP) or hyperpolarizing (IPSP).
  • EPSP: depolarizing postsynaptic potential that moves the membrane potential toward threshold.
  • IPSP: hyperpolarizing postsynaptic potential that moves the membrane potential away from threshold.
  • Summation of graded potentials determines the overall membrane potential change.

Summation of Graded Potentials

  • All graded potentials produce small changes in voltage that can summate.
  • The total change determines whether the neuron reaches threshold and fires an action potential.
  • Example: If several inputs produce a net depolarization of +15 mV15\ \text{mV}, from Vrest≈−70 mVV_{rest} \approx -70\ \text{mV} to V≈−55 mVV \approx -55\ \text{mV}, the neuron can reach threshold and fire.
  • For receptor potentials, threshold is not a factor because the change directly causes neurotransmitter release.
  • Generator potentials can initiate action potentials in the sensory neuron axon.
  • Postsynaptic potentials can initiate an action potential in the axon of other neurons.

Initial Segment and Spatial/Temporal Summation

  • Signal conversion: electrical signals to chemical signals and back involves transient increases or decreases in membrane voltage.
  • To cause lasting change in the target cell, multiple signals summate at the initial segment of the axon.
    • For sensory neurons (no cell body between dendrites and axon), the initial segment is directly adjacent to dendritic endings.
    • For other neurons, the axon hillock serves as the initial segment.
    • These locations have a high density of voltage-gated Na extsuperscript{+} channels to initiate the depolarizing phase of the action potential.
  • Types of summation:
    • Spatial summation: several graded potentials arrive at different locations on the neuron and sum.
    • Temporal summation: multiple graded potentials from a single cell arrive in rapid succession at the same location and sum over time.
    • They can act together, producing larger depolarizations or hyperpolarizations.
  • Visual example (Figure 12.26):
    • Point A: several excitatory postsynaptic potentials (EPSPs) summate to a large depolarization.
    • Point B: a mix of EPSPs and IPSPs results in a different final membrane potential.

Synapses and Neurotransmitter Release

  • Synapses come in two main types: chemical and electrical.
    • Chemical synapse: a chemical signal (neurotransmitter) is released from one cell and affects the other cell.
    • Electrical synapse: direct ionic connection allows ions to pass between cells, causing synchronized depolarization.
  • Focus here: chemical synapses (the majority in the nervous system).
  • Common synapse features:
    • Presynaptic element: neurotransmitter packaged in vesicles.
    • Synaptic cleft: the extracellular space between cells where neurotransmitter diffuses.
    • Receptor proteins on the postsynaptic membrane.
  • Neurotransmitter release process:
    • Action potential arrives at axon terminals.
    • Voltage-gated Ca extsuperscript{2+} channels open in the presynaptic membrane.
    • Ca extsuperscript{2+} causes vesicle fusion with the presynaptic membrane.
    • Neurotransmitter is released by exocytosis into the synaptic cleft.
    • Neurotransmitter diffuses across the cleft to bind receptors on the postsynaptic membrane.
    • Receptors are specific for each neurotransmitter (key-and-lock concept).
    • After signaling, neurotransmitter is cleared from the synapse by enzymatic degradation, neuronal reuptake, or glial reuptake.
  • Neuromuscular junction (NMJ) example:
    • Presynaptic element: motor neuron's axon terminals.
    • Neurotransmitter: acetylcholine (ACh).
    • Synaptic cleft: space where ACh diffuses.
    • Receptor: nicotinic acetylcholine receptor (nAChR).
    • Postsynaptic element: sarcolemma of muscle cell.
    • Elimination: acetylcholinesterase degrades ACh.

Neurotransmitter Systems

  • Cholinergic system (ACh):
    • Receptors: nicotinic and muscarinic.
    • Nicotinic receptors: located at NMJ and elsewhere; ligand-gated cation channels that cause depolarization when activated.
    • Muscarinic receptors: metabotropic; subtypes can cause depolarization or hyperpolarization depending on the subtype.
    • Drugs: nicotine binds to nicotinic; muscarine binds to muscarinic; cross-reactivity is receptor-specific (nicotine does not bind muscarinic, and muscarine does not bind nicotinic).
  • Amino acid neurotransmitters:
    • Glutamate (Glu): excitatory; receptor binding generally leads to depolarization.
    • GABA (gamma-aminobutyric acid) and Glycine (Gly): inhibitory; receptor binding leads to hyperpolarization.
    • Reuptake: amino acids are cleared from the synapse by transporters, often in presynaptic neurons or surrounding glia, for reuse.
  • Biogenic amines:
    • Serotonin (5-HT): derived from tryptophan; serotonergic system with its own receptors; reuptake into presynaptic neuron for reuse.
    • Dopamine: derived from tyrosine; dopaminergic system with D1 (typically excitatory) and D2 (inhibitory) receptors; removed by presynaptic transporters.
    • Norepinephrine (NE) and Epinephrine (E): derived from tyrosine; adrenergic receptors (alpha and beta); reuptake into presynaptic cell.
    • Epinephrine is also released by the adrenal gland as a hormone.
    • Terminology: epinephrine = adrenaline; norepinephrine = noradrenaline.
  • Neuropeptides:
    • Chains of amino acids; e.g., met-enkephalin (five amino acids), beta-endorphin (thirty-one amino acids).
    • Often co-released with another neurotransmitter and can act as hormones in other systems (e.g., VIP, Substance P).
  • Receptor effects depend on receptor type:
    • If no receptor is present, the neurotransmitter has no effect.
    • ACh binding to nicotinic receptor causes depolarization (cation channel opening, Na extsuperscript{+} influx).
    • ACh binding to muscarinic receptor can cause either depolarization or hyperpolarization depending on the receptor subtype.
    • Glutamate receptors generally depolarize.
    • Glycine and GABA receptors generally hyperpolarize.
    • Dopamine receptors: D1 (excitatory) vs D2 (inhibitory).
  • Receptors categories (Figure 12.28):
    • Ionotropic receptors: ligand-gated ion channels (e.g., nicotinic ACh receptor, GABA extsuperscript{A} receptor, certain Glu receptors).
    • Metabotropic receptors: G protein-coupled receptors that initiate intracellular signaling cascades via second messengers.
  • Second messengers in metabotropic signaling:
    • Common second messengers: cAMP\text{cAMP} and IP3\text{IP}_3.
    • Adenylate cyclase (enzyme) makes cAMP\text{cAMP}; Phospholipase C makes IP3\text{IP}_3.
    • The second messenger activates intracellular processes, including opening/closing ion channels, metabolic changes, and gene transcription.
    • In neurons, these changes can strengthen synaptic connections and contribute to learning and memory.
  • Table 12.3 (summary): characteristics of neurotransmitter systems, including transmitter, receptors, elimination, and postsynaptic effects.

Neurotransmitter Release: Summary of Systems and Effects

  • Release process is common to chemical synapses:
    • Arrival of action potential at axon terminal → Ca extsuperscript{2+} influx via voltage-gated Ca extsuperscript{2+} channels → vesicle fusion and neurotransmitter release → diffusion across cleft → receptor activation → postsynaptic response.
  • Elimination mechanisms ensure transmitter clearance and signal termination:
    • Enzymatic degradation (e.g., acetylcholinesterase for ACh).
    • Reuptake into presynaptic neuron or glial cells.
  • Receptor effects on postsynaptic neurons:
    • Ionotropic receptors typically produce fast, short-lived responses (direct ion flow).
    • Metabotropic receptors produce slower, longer-lasting effects through second messengers.
  • Example table entries (from Interactive content):
    • Cholinergic system: transmitter ACh; receptors: nicotinic and muscarinic; elimination: acetylcholinesterase; postsynaptic effect: nicotinic depolarization; muscarinic varies by subtype.
    • Amino acids system: transmitters Glu, Gly, GABA; receptors: Glu receptors, Gly receptors, GABA receptors; elimination: reuptake (Glu, GABA, Gly); postsynaptic effect: Glu depolarization; Gly and GABA hyperpolarization.
    • Biogenic amine system: transmitters 5-HT, dopamine, NE, epinephrine; receptors: various (e.g., D1, D2; alpha/beta); elimination: presynaptic reuptake; postsynaptic effect: variable by receptor type (D1 typically depolarizing, D2 typically hyperpolarizing).
    • Neuropeptide system: transmitters Met-enkephalin, beta-endorphin, VIP, Substance P, etc.; receptors: diverse peptide receptors; elimination: peptidases and uptake mechanisms; postsynaptic effect: variable and often modulatory.

Receptors: Ionotropic vs Metabotropic

  • Ionotropic receptors:
    • Ligand-gated ion channels; rapid responses.
    • Examples: nicotinic ACh receptor, Glu receptors (certain subtypes), GABA
      type A receptor, glycine receptor.
  • Metabotropic receptors:
    • G protein-coupled receptors; slower, modulatory effects via second messengers.
    • Involve receptor, G protein, and effector protein; second messengers include cAMP\text{cAMP} and IP3\text{IP}_3.
  • Overall significance: The same neurotransmitter can have different effects depending on receptor type and location, shaping excitation or inhibition and plasticity.

Neurophysiology and Pathology: Proteins and Diseases

  • Proteins must fold into correct three-dimensional shapes to function properly; misfolding leads to loss of function and potential toxicity.
  • Proteopathies link protein misfolding/aggregation to disease:
    • Alzheimer's disease: beta-amyloid plaques in the cerebral cortex.
    • Parkinson's disease: accumulation of alpha-synuclein in the substantia nigra.
    • Protein misfolding can accumulate and become toxic, rather than just causing loss of function.
  • Broader examples of proteopathic processes:
    • Creutzfeldt–Jakob disease (human prion disease) involves amyloid-like plaques.
    • Other organ diseases show proteostasis issues (e.g., cystic fibrosis, type 2 diabetes).
  • Therapeutic implication: targeting protein accumulation early (even during production) may offer strategies to treat or delay these diseases.

Connections to Core Concepts and Real-World Relevance

  • Core principle: neuronal communication is a cascade from electrical signals (graded potentials and action potentials) to chemical signaling (neurotransmitter release) and back to electrical responses in the postsynaptic cell.
  • The net effect (excitatory vs inhibitory) depends on receptor type, not just the transmitter itself, highlighting the importance of receptor distributions and signaling pathways in shaping neural circuits.
  • Learning and memory: second-messenger cascades and changes in gene transcription can alter synaptic strength, potentially supporting long-term changes in connectivity.
  • Practical relevance: understanding NMJ transmission explains how motor commands translate into muscle contraction and how drugs or toxins that alter ACh signaling (e.g., acetylcholinesterase inhibitors) affect neuromuscular function.

Quick Reference: Key Quantities and Concepts

  • Resting potential: Vrest≈−70 mVV_{rest} \approx -70\ \text{mV}
  • Threshold example: if depolarization adds +15 mV15\ \text{mV} to the membrane potential, the membrane moves from Vrest=−70 mVV_{rest} = -70\ \text{mV} to V=−55 mVV = -55\ \text{mV}, reaching threshold.
  • Ion movements driving graded potentials:
    • Depolarization: inward flow of Na+\text{Na}^+ or Ca2+\text{Ca}^{2+}
    • Hyperpolarization: outward flow of K+\text{K}^+ or inward flow of Cl−\text{Cl}^-
  • Key receptor classes and their general effects:
    • Ionotropic receptors: fast responses via direct ion flow.
    • Metabotropic receptors: slower, diverse effects via second messengers (e.g., cAMP\text{cAMP}, IP3\text{IP}_3).
  • Neurotransmitter systems and their primary transmitters:
    • Cholinergic: Acetylcholine (ACh)
    • Amino acids: Glutamate (Glu), GABA, Glycine (Gly)
    • Biogenic amines: Serotonin (5-HT), Dopamine, Norepinephrine (NE), Epinephrine (E)
    • Neuropeptides: Met-enkephalin, Beta-endorphin, VIP, Substance P, etc.