Lecture 8:Membrane Mechanisms Flashcards
What factors contribute to the variety of firing patterns observed in neurons,
and how can neurons switch between different firing patterns?
AP Firing Patterns
- VARIETY OF TEMPORAL FIRING PATTERNS: Many different firing patterns are observed in neurons.
- PATTERN SWITCHING: Some neurons can SWITCH from one firing pattern to another.
Why can’t the variety of firing patterns observed in neurons be explained by a single type of voltage-gated Na⁺ and K⁺ channels? = 3
AP Firing Patterns
- VARIETY OF TEMPORAL FIRING PATTERNS: Many different firing patterns are observed in neurons.
- PATTERN SWITCHING: Some neurons can SWITCH from one firing pattern to another.
- This variety CANNOT BE EXPLAINED by just one type of VOLTAGE-GATED Na⁺ and K⁺ CHANNELS
firing patterns on slide 4
Transient:
DELAY
ADAPTING SPIKING
RAPIDLY ADAPTING SPIKING
TRANSIENT STUTTERING
TRANSIENT SLOW WAVE BURSTING
Steady State:
STEADY STATE SILENCE
NON-ADAPTING SPIKING
PERSISTENT STUTTERING
PERSISTENT SLOW WAVE BURSTING
Silence:
DELAY
STEADY STATE SILENCE
Spiking:
ADAPTING SPIKING
NON-ADAPTING SPIKING
Stuttering:
TRANSIENT STUTTERING
PERSISTENT STUTTERING
Bursting:
TRANSIENT SLOW WAVE BURSTING
PERSISTENT SLOW WAVE BURSTING
What are some of the membrane
mechanisms involved in modulation of AP
firing patterns? =
- Voltage-Gated Ion Channels:
- Na⁺ Channels
- K⁺ Channels
- Ca²⁺ Channels - Ion Channel Kinetics:
- Activation Rates
- Inactivation Rates - Ion Channel Distribution:
- Spatial Localization - Synaptic Input:
- Excitatory Inputs
- Inhibitory Inputs - Modulatory Signals:
- Neurotransmitters
- Neuropeptides
- Hormones - Intracellular Signaling:
- Second Messengers
- Protein Kinases - Membrane Properties:
- Resting Membrane Potential
- Capacitance
- Conductance - Channel Interactions:
- SNARE Proteins
Different types of ion channels and receptors: 4
- ‘Ligand-Gated:’
— Activated by: Binding of specific molecules (ligands) such as neurotransmitters.
— Example: NMDA Receptors, AMPA Receptors. - ‘Voltage-Gated:’
— Activated by: Changes in membrane potential.
— Example: Na⁺ Channels, K⁺ Channels, Ca²⁺ Channels. - ‘Mechanically-Gated:’
— Activated by: Physical deformation of the membrane (e.g., stretching or pressure).
— Example: Mechanoreceptors in sensory neurons. - ‘Always Open:’
— Activated by: Always open under normal conditions, allowing ions to pass through continuously.
— Example: Leak Channels (e.g., K⁺ Leak Channels).
Basic Chemical Neurotransmission
PRESYNAPTIC: 2
- RELEASE OF NEUROTRANSMITTER:
- Via CA²⁺-DEPENDENT EXOCYTOSIS. - VOLTAGE-GATED CA²⁺ CHANNELS:
- Trigger the release of neurotransmitters by allowing Ca²⁺ influx into the presynaptic terminal.
Post-Synaptic Receptors - How does receptor variability influence the action of neurotransmitters on target cells? = 5
- BIND SPECIFIC NEUROTRANSMITTERS
- HUGE VARIABILITY (subunits/subtypes)
- RECEPTOR DETERMINES ACTION on target cell
- ‘IONOTROPIC vs METABOTROPIC ACTION’
- Example: nicotinic acetylcholine
receptor (nAChR)
What are the differences between homomeric and heteromeric nAChRs in terms of their subunit composition?
Homomeric nAChRs
HOMOMERIC nAChRs: Composed of identical subunits.
EXAMPLE: NICOTINIC ACETYLCHOLINE RECEPTOR (nAChR)
Heteromeric nAChRs
HETEROMERIC nAChRs: Composed of different subunits.
EXAMPLE: NICOTINIC ACETYLCHOLINE RECEPTOR (nAChR)
How do excitatory and inhibitory ‘ionotropic receptors’ differ in their effects on membrane potential? = 4
Ionotropic Receptors
- LIGAND-GATED ION CHANNELS: Activated by binding of neurotransmitter.
- FAST ACTION: Rapid response to neurotransmitter binding.
…3. ‘EXCITATORY’: Increase Na⁺ PERMEABILITY.
…4. ‘INHIBITORY’: Increase Cl⁻ OR K⁺ PERMEABILITY.
How do NMDA and AMPA receptors differ in their response to glutamate and their roles in neurotransmission? 6
- ‘Different Ionotropic Receptors for the Same Neurotransmitter.’
…2. EXAMPLE: GLUTAMATE RECEPTORS
…3. GLUTAMATE: Most abundant neurotransmitter in CNS of vertebrates. - DISTINCTION BETWEEN NMDA AND NON-NMDA (AMPA) RECEPTORS:
…5. NMDA RECEPTORS: Named after NMDA (N-Methyl D-Aspartate), a powerful agonist.
…6. AMPA RECEPTORS: Named after AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid), a powerful agonist.
How does zinc modulation affect NMDA receptor function and its potential role in preventing glutamate excitotoxicity? = 7
- Receptor action Can Be Modulated
- MODULATION OF VOLTAGE-GATED ION CHANNELS: By trace metals.
- EXAMPLE: NMDA RECEPTOR AND ZINC
…4. PATCH CLAMP IN MOUSE HIPPOCAMPAL NEURONS AND OOCYTES:
— 5. Responses to NMDA strongly antagonized by zinc.
- FUNCTION OF MODULATION BY ZINC:
…7. PREVENTING GLUTAMATE EXCITOTOXICITY
How do zinc and copper modulate voltage-gated ion channels, and what effects do these trace metals have on neuronal firing? = 6
- Modulation of Receptors
- MODULATION OF VOLTAGE-GATED ION CHANNELS BY TRACE METALS: Zinc and copper.
- INHIBITION OF VOLTAGE-GATED CALCIUM CHANNEL CURRENTS
- REDUCTION OF NEURONAL FIRING:
…5. Effect on K⁺ CURRENTS.
EXPERIMENTAL MODEL:
…6. Rat olfactory bulb neurons in culture, using VOLTAGE CLAMP and INTRACELLULAR RECORDINGS.
How does a rise in calcium contribute to the inactivation of ion channels, and what are the roles of calcium binding and calcineurin activation in this process? = 5
- Modulation of Ion Channels
- DIFFERENT MECHANISMS OF INACTIVATION:
- RISE IN CALCIUM (SELF-LIMITING)
….4….”CALCIUM BINDING” 1A. CALCIUM BINDING DIRECTLY TO ITS OWN CHANNEL: Causes CLOSURE.
….5…..”DEPHOSPHORYLATION” 1B. CALCIUM ACTIVATES CALCINEURIN: This dephosphorylates channels, causing INACTIVATION.
How does the refractory period of ion channels contribute to the absolute and relative refractory periods in neurons? = 4
- DIFFERENT MECHANISMS OF INACTIVATION:
- SOME CHANNELS HAVE REFRACTORY PERIOD
…3.CHANNELS CLOSED AND NOT AVAILABLE
…4. RESULTS IN ABSOLUTE VS RELATIVE REFRACTORY PERIOD IN A NEURON
What are the implications of the refractory period of Na⁺ channels for channel availability and neuronal excitability? = 6
- implications of the Refractory Period of Na⁺ Channels
- PROPORTION OF AVAILABLE CHANNELS
…3. % OF Na⁺ CHANNELS AVAILABLE: About 40% of voltage-gated Na⁺ channels are inactivated at normal resting potential.
…4. HYPERPOLARIZATION MAKES MORE VOLTAGE-GATED Na⁺ CHANNELS AVAILABLE: For opening by a subsequent depolarization.
…5. LEADS TO POST-INHIBITORY REBOUND: When hyperpolarization results in increased availability of Na⁺ channels.
…6. AT NORMAL RESTING POTENTIAL: Not all voltage-gated Na⁺ channels are available.
Post-Inhibitory Rebound
What causes increased firing in post-inhibitory rebound, and how does this relate to the availability of Na⁺ channels? 3
- INCREASED FIRING AFTER A PERIOD OF INHIBITION
…2. CAUSED BY INCREASED NUMBER OF AVAILABLE Na⁺ CHANNELS:
– Fewer inactivated channels.
…3. EXAMPLE: RETINAL GANGLION CELLS.
No Refractory Period: K⁺ Channels
How does the voltage clamp technique differentiate between Na⁺ and K⁺ currents, and what is unique about the inactivation of K⁺ channels in axons? = 6
- CLASSICAL VOLTAGE-GATED K⁺ CHANNELS IN AXONS DO NOT INACTIVATE:
…2.SOURCE UNKNOWN.
- VOLTAGE CLAMP TECHNIQUE:
…4. RECORDS MEMBRANE CURRENTS WHEN Vm IS CONTROLLED.
…5. EARLY INWARD CURRENT: Na⁺ charge movement.
…6. DELAYED OUTWARD CURRENT: K⁺ charge movement.
K⁺ Channels
What are the effects of tetrodotoxin (TTX) and tetraethyl ammonium (TEA) on ion channels, and how do selective blockers contribute to the study of K⁺ currents?
= 6
- SELECTIVE BLOCKERS ALLOW K⁺ CURRENTS TO BE ISOLATED:
…2. SOURCE UNKNOWN. - TETRODOTOXIN (TTX):
…4. BLOCKS VOLTAGE-GATED Na⁺ CHANNELS. - TETRAETHYL AMMONIUM (TEA):
…6. BLOCKS VOLTAGE-GATED K⁺ CHANNELS.
Which K⁺ channel subtypes exhibit refractory periods and inactivation,
and how does the blocking of Na⁺ current with toxins relate to these channels?
- Some K+ channel subtypes do show refractory
periods - A-TYPE K⁺ CHANNELS (Kv CHANNELS) SHOW INACTIVATION:
…3. SOURCE UNKNOWN. - Na⁺ CURRENT BLOCKED WITH TOXI
A-TYPE K⁺ CHANNELS REGULATE INTERSPIKE INTERVAL:
How do A-type K⁺ channels affect the interspike interval and the range of action potential firing rates? = 7
- A-TYPE K⁺ CHANNELS ONLY AVAILABLE DURING AFTER-POTENTIAL:
…2. Will delay depolarization.
- Voltage-Gated K⁺ Channels (A-Type) ARE INACTIVATED WHEN Vm < -50 mV:
…4. Become available during afterhyperpolarization.
- During Next Depolarization Towards Threshold:
…6. Outward current through A-type channels LENGTHENS INTERVALS BETWEEN APs.
…7. Gives Greater Range of AP Firing Rates.
A-TYPE K⁺ CHANNELS CAN CAUSE DELAYED FIRING:
How do A-type K⁺ channels affect the timing and initiation of action potentials during different membrane potentials?
= 8
- A-type K+ channels
- At NORMAL Vm:
…3. Immediate TRAIN OF ACTION POTENTIALS following depolarization stimulus.
- At HYPERPOLARIZATION:
..5. FIRST DELAY BEFORE ACTION POTENTIALS:
……6. Caused by A-TYPE K⁺ CHANNELS opening rapidly at depolarization.
……7. Generate SHORT OUTWARD CURRENT, delaying the opening of Na⁺ CHANNELS.
…..8. A-TYPE CHANNELS ARE INACTIVATED AT NORMAL RESTING POTENTIAL.
HOW DOES DAMPENED FUNCTION AND EXPRESSION OF Kv CHANNELS IN NEUROPATHIC PAIN AFFECT THE FIRING RATES OF PRIMARY AFFERENT NEURONS AND PAIN PERCEPTION?
A-TYPE K⁺ CHANNELS IN PATHOLOGY:
= 4
- IN NEUROPATHIC PAIN:
- Kv CHANNELS SHOW DAMPENED FUNCTION AND EXPRESSION:
…3. May INCREASE FIRING OF PRIMARY AFFERENT NEURONS involved in nociception.
….4. Potentially leads to HYPERSENSITIVITY.
HOW DOES THE FUNCTION AND EXPRESSION OF Kv1.2 AND Kv1.4 CHANNELS IN NEUROPATHIC PAIN MODELS AFFECT ACTION POTENTIAL FIRING AND INTERSPIKE INTERVAL?
Kv CHANNELS AND THEIR FUNCTION: 7
- αNTID is responsible for FAST N-TYPE INACTIVATION in Kv1.4 channels.
- βNTID of the accessory Kvβ1 SUBUNIT confers N-type inactivation to Kv1.1 and Kv1.2 channels.
- Kv1.4 CHANNELS:
…4. Found in SOMA and AXONS, including the JUXTA PARANODAL REGION of the NODES OF RANVIER.
…5. LOW VOLTAGE-ACTIVATING, potentially regulating AP FIRING and INTERSPIKE INTERVAL.
- IN NEUROPATHIC PAIN ANIMAL MODELS:
…7. Kv1.2 and Kv1.4 channels exhibit DAMPENED FUNCTION and EXPRESSION.
HOW DOES THE ACTIVATION OF Ca²⁺-ACTIVATED K⁺ CHANNELS CONTRIBUTE TO FIRING RATE ADAPTATION IN NEURONS?
Firing Rate Adaptation = 4
- Depolarizing Stimulus causes Ca²⁺ INFLOW via VOLTAGE-GATED Ca²⁺ CHANNELS.
- This ACTIVATES Ca²⁺-ACTIVATED K⁺ CHANNELS, leading to LATE HYPERPOLARIZATION.
- Ca²⁺-ACTIVATED K⁺ CHANNELS:
- Involved in ADAPTING FIRING RATES by contributing to the LATE HYPERPOLARIZATION.
WHAT EVIDENCE SUPPORTS THE ROLE OF Ca²⁺-ACTIVATED K⁺ CHANNELS IN FIRING RATE ADAPTATION?
Evidence of Involvement of Ca²⁺-Activated K⁺ Channels in Firing Rate Adaptation = 5
- Provides EVIDENCE for the involvement of Ca²⁺-ACTIVATED K⁺ CHANNELS in firing rate adaptation.
- Normal Firing Rate Adaptation:
…3. Ca²⁺ ENTRY BLOCKED: Shows that the adaptation process relies on Ca²⁺-ACTIVATED K⁺ CHANNELS.
- Source Unknown:
…5. EBIO enhances the EFFECTIVENESS of Ca²⁺-ACTIVATED K⁺ CHANNELS, indicating their role in firing rate adaptation.
Burst Firing:
HOW DO T-TYPE Ca²⁺ CHANNELS AFFECT BURST FIRING AND EXCITABILITY?
= 5
- Example 1: Low Threshold Ca²⁺ Channels (T-type)
- INACTIVATED (NOT AVAILABLE) at NORMAL MEMBRANE POTENTIAL.
- AVAILABLE at HYPERPOLARIZED MEMBRANE POTENTIAL (e.g., -75 mV).
- DIFFERENT RESPONSE to the same DEPOLARIZING STIMULUS due to channel availability.
- FIRING PROPERTIES and EXCITABILITY change when DIFFERENT CHANNELS are made available or unavailable.
HOW DO H-TYPE CHANNELS CONTRIBUTE TO BURST FIRING AND HYPERPOLARIZATION
Burst Firing: 6
- Small Depolarization opens Ca²⁺ Voltage-Gated Channels and subsequently the “USUAL” Na⁺ Voltage-Gated Channels.
- Example 2: H-Type Channels
…3. OPEN in response to HYPERPOLARIZATION, causing SMALL DEPOLARIZATION.
…4. OPEN to both Na⁺ and K⁺.
…5. STRONG DEPOLARIZATION from action potentials CLOSES H-Type Channels and Ca²⁺ Voltage-Gated Channels.
…6 Allows HYPERPOLARIZATION to develop, leading to another BURST.
So ionotropic receptors and ion
channels show large variety and their action can be modulated in several ways
So ionotropic receptors and ion
channels show large variety and their action can be modulated in several ways
WHAT ARE THE MAIN MECHANISMS OF MODULATION FOR IONOTROPIC RECEPTORS AND ION CHANNELS?
ionotropic Receptors and Ion Channels:
- LARGE VARIETY in types and functions.
- MODULATION of their action can occur through several mechanisms.
Key Points:
- IONOTROPIC RECEPTORS: Ligand-gated ion channels activated by neurotransmitters. They can be EXCITATORY (increase Na⁺ permeability) or INHIBITORY (increase Cl⁻ or K⁺ permeability).
- ION CHANNELS:
- VOLATAGE-GATED: Activated by changes in membrane potential.
- LIGAND-GATED: Activated by neurotransmitter binding.
- MECHANICALLY-GATED: Activated by mechanical forces.
- ALWAYS OPEN: Continually allow ions to pass through.
Metabotropic Receptors: 4
HOW DO METABOTROPIC RECEPTORS DIFFER FROM IONOTROPIC RECEPTORS IN TERMS OF MECHANISM AND EFFECTS?
- INDIRECT PATHWAY: Do not directly open ion channels.
- OFTEN INVOLVES G-PROTEIN PATHWAY: Activate G-proteins that initiate intracellular signaling.
- ENZYME CASCADE: Leads to a chain reaction of events within the cell.
- SLOW ACTION, COMPLEX EFFECTS: Effects are longer-lasting and more complex compared to ionotropic receptors.
Ligand-Gated Ion Channels: 3
- NEUROTRANSMITTER BINDS:
- The Neurotransmitter binds to the receptor. - CHANNEL OPENS:
- The channel undergoes a conformational change and opens. - IONS FLOW ACROSS THE MEMBRANE:
- Ions move through the channel and across the membrane.
G-Protein-Coupled Receptors: 5
- NEUROTRANSMITTER BINDS: Neurotransmitter binds to the receptor.
- G-PROTEIN IS ACTIVATED: The binding activates the G-protein.
- G-PROTEIN SUBUNITS OR INTRACELLULAR MESSENGERS MODULATE ION CHANNELS: The activated G-protein subunits or messengers influence ion channels.
- ION CHANNELS OPEN: The ion channels open as a result of modulation.
- IONS FLOW ACROSS THE MEMBRANE: Ions move through the open channels and across the membrane.
G-Proteins: 4
WHAT IS THE FUNCTION OF G-PROTEINS IN THE ACTIVATED AND INACTIVATED STATES, AND HOW DOES THIS AFFECT CELLULAR SIGNALING?
- SPECIALIZED PROTEINS: G-proteins are specialized proteins involved in cell signaling.
- BIND NUCLEOTIDES: They can bind guanosine triphosphate (GTP) and guanosine diphosphate (GDP).
…3. GTP ACTIVATED STATE: When bound to GTP, the G-protein is in its activated state.
…4. GDP INACTIVATED STATE: When bound to GDP, the G-protein is in its inactivated state.
Metabotropic Receptors: 2
HOW DO G-PROTEINS MODULATE ION CHANNELS DIRECTLY IN THE SHORT-CUT PATHWAY OF METABOTROPIC RECEPTORS?
- SHORT-CUT PATHWAY:
– Metabotropic receptors can use a short-cut pathway. - G-PROTEINS MODULATE ION CHANNELS DIRECTLY:
– G-proteins can modulate ion channels directly without requiring intermediate steps.
Metabotropic Receptors: Modulation of Excitability …5
HOW DOES THE ACTIVATION OF β-ADRENERGIC RECEPTORS LEAD TO CHANGES IN POTASSIUM CHANNEL FUNCTION THROUGH THE G-PROTEIN PATHWAY?
- B RECEPTOR BINDING TO NE: Noradrenaline (NE) binds to β-adrenergic receptors.
- G-PROTEIN ACTIVATION: This activates the G-protein.
- ATP TO cAMP: ATP is converted to cyclic AMP (cAMP) by adenyl cyclase.
- cAMP ACTIVATES PROTEIN KINASE: cAMP activates protein kinase.
- PROTEIN KINASE MODULATES POTASSIUM CHANNEL: Protein kinase modulates potassium channels, affecting their function and thereby modulating neuronal excitability.
Metabotropic Receptors: G-Protein Second Messengers = 3
HOW DO G-PROTEIN SECOND MESSENGERS AFFECT MEMORY FORMATION AND SYNAPTIC PLASTICITY IN NEURONS?
- G-PROTEIN SECOND MESSENGERS: Involved in signaling pathways inside the neuron.
- EFFECTS INSIDE THE NEURON: Influence various cellular processes such as enzyme activation, changes in ion channel activity, and alterations in gene expression.
- ROLE IN MEMORY: Critical for processes like synaptic plasticity and memory formation, impacting long-term potentiation (LTP) and other memory-related functions.
Metabotropic receptors
G-protein second messengers: effects inside the neuron
diagram on slide 33
Metabotropic Receptors: G-Protein Second Messengers
HOW DO G-PROTEIN SECOND MESSENGERS INFLUENCE GENE EXPRESSION AND TRANSCRIPTIONAL REGULATION IN NEURONS?
2
- G-PROTEIN SECOND MESSENGERS: Affect various intracellular processes in neurons.
- DOWNSTREAM TRANSCRIPTION REGULATION: G-protein signaling can influence gene expression by regulating transcription factors and other molecular pathways.
Metabotropic receptors
G-protein second messengers: effects inside the neuron
Downstream transcription
regulation of genes
diagram on slide 34
Metabotropic Receptors: Why Have Them? = 3
WHAT ARE THE ADVANTAGES OF HAVING METABOTROPIC RECEPTORS IN TERMS OF SIGNAL AMPLIFICATION AND CELLULAR MODULATION?
- SIGNAL AMPLIFICATION MECHANISM: Metabotropic receptors can amplify signals through second messenger systems, leading to significant and prolonged changes within the cell.
- MODULATION: They allow for modulation of neuron excitability and synaptic strength over a longer time frame compared to ionotropic receptors.
- VARIETY OF EFFECTS: Through diverse signaling pathways, metabotropic receptors can influence various cellular processes, including gene expression, protein synthesis, and long-term changes in synaptic plasticity.
Why have metabotropic
receptors?
ANSWER:
Signal amplification
mechanism
the diagram on slide 35
HOW DO THE TIME-COURSE AND MECHANISMS OF IONOTROPIC AND METABOTROPIC RECEPTORS DIFFER IN TERMS OF THEIR IMPACT ON EPSPs AND EXCITABILITY?
Time-Course Differences: Ionotropic vs Metabotropic Receptors =
- iONOTROPIC RECEPTORS:
- FAST EPSPs: Cause rapid excitatory postsynaptic potentials.
- SHORT-TERM EFFECTS: Act quickly, leading to immediate changes in membrane potential.
- DIRECT ACTION: Directly open ion channels upon neurotransmitter binding, allowing ions to flow across the membrane.
- METABOTROPIC RECEPTORS:
- SLOW EPSPs: Cause slower excitatory postsynaptic potentials.
- LONG-TERM EFFECTS: Have longer-lasting effects, influencing cellular processes and synaptic plasticity over time.
- INDIRECT ACTION: Utilize G-protein-coupled pathways and second messengers to modulate ion channels and other intracellular targets, resulting in a more gradual and sustained response.
time-Course Differences: Ionotropic vs Metabotropic Receptors
diagram on slide 36
Other Chemical Messengers = 9
WHAT ROLES DO GROWTH FACTORS LIKE NGF AND BDNF PLAY IN NEURONAL FUNCTION AND DEVELOPMENT?
- NEURONS AND GLIA:
- Have receptors for signals beyond neurotransmitters.
- CHEMICAL SIGNALS:
- NERVE GROWTH FACTOR (NGF): Involved in neuron survival and differentiation.
- BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF): Plays a role in synaptic plasticity and neurogenesis.
- OTHERS: NT-3, CNTF, EGF, FGF, etc.
- RECEPTORS:
- TYROSINE KINASE (trk) PROTEIN FAMILY: Many growth factor receptors are part of this family.
- ROLES: Critical for neuron growth, development, and survival.
Ion channel diversity
underlies action potential firing pattern
Ion channel diversity is key to the variety of action potential firing patterns.
