Receptor Structure and Function
introduction
- ligand-gated channels are heteromultimers
- heteromultimeric: assembled from different types or isoforms of subunits in a given receptor
- for each class of receptor, there can be many different types of subunits
- subunits can be expressed differentially, based on location or development
- differential expression: means of fine-tuning receptor function
- ligand-gated ion channels are encoded by related genes
- family 1
- transmitters: acetylcholine, GABAA, glycine, 5HT-3 (serotonin)
- structure: pentamers, each subunit with 4 transmembrane domains, external N- and C-termini
- family 2: glutamate receptors
- transmitters: AMPA, kainite, NMDA
- structure: tetramers, each subunit with 3 transmembrane domains, external N and internal C
- amino termini: serve as binding pockets for transmitters
- ion selectivity
- factors: ion size, ion charge
- examples
- acetylcholine receptor: rings of (-) amino acids form an attractive pathway for cation flow
- GABAA receptor: rings of (+) amino acids form an attractive pathway for anion flow
- inhibitory vs. excitatory receptors
- excitatory: often depolarize the neuron
- inhibitory: often hyperpolarize the neuron
topographic organization
- receptive field
- receptive field: the part of sensory space that activates a neuron
- touch receptor: dimensions related to space (X, Y, Z)
- sound receptor: dimensions related to sound (frequency, amplitude)
- photoreceptor: dimensions related to light (wavelength, visual space, direction)
- sensory space: the part of the sensory modality that the receptor will respond to
- outside a particular band of a particular modality, the receptor will not respond
- encoding of stimulus location
- acuity: the ability to distinguish stimuli
- lateral inhibition: the use of neuronal trees to inhibit other neurons
- function: reduces background noise
sharpens stimulus
- mechanism: neurons cause slight inhibition of adjacent neurons, reducing input by all
- tactile input: stimulus contacts several adjacent neurons
- receptor input: graded response (bell curve) based on location of strongest aspect of input
- CNS input: due to reduction in all inputs, only the most central neurons pass information
- topography
- location: brain interpretation of signals is entirely dependent on topographical organization within brain
- size: proportional to number of receptors in a given region
glutamate receptors
- glutamate: amino acid common to all cells, many proteins
- use: half of the neurons in the body use it as a primary neurotransmitter
- targets: various types of receptor
- AMPA receptors: fast synaptic excitation
- type: excitatory
- distribution: workhorse receptor, in nearly every CNS region
- specificity: nonspecific cation channel (monovalent cations Na+, K+)
- EAMPA: near 0 mV
- kinetics: rapid; excitatory post-synaptic current (EPSC) will last only a few milliseconds
- NMDA receptors: mediation of Ca2+ influx
- type: excitatory
- specificity: nonspecific cation channel (Na+, K+, and Ca2+)
- ENMDA: near 0 mV
- kinetics: slow; requires ~10 ms to open, hundreds of ms to close
- distinguishing NMDA receptors from AMPA receptors
- slower kinetics
- binds glutamate, opens in ~10 ms, takes hundreds of ms to close
- EPSC is much slower than the membrane time constant
- voltage dependence
- at potentials negative to rest, Mg2+ sits in the ion channel pore, preventing excitation
- at depolarizing potentials, Mg2+ is driven out, thus only opening in an already excited membrane
- permeability to Ca2+
- extracellular Ca2+ is quite high relative to the extremely low intracellular concentrations
- Ca2+ ions thus have powerful signaling properties in neurons, mediating long-term changes in synapse
- actions of Ca2+ in neurons
- activation of Ca2+-activated K+ channels, hyperpolarizing and inhibiting the neuron
- activation of Ca2+-sensitive protein kinases (Ca2+-calmodulin-dependent PK) or phosphatases (calcineurin)
- actions on ion channels, altering their function
- actions as coincidence detectors
- only open with the coincident activity of pre- and post-synaptic neurons
- pre-synaptic: release of glutamate
- post-synaptic: membrane depolarization
- signal this as changes in long term potentiation (LTP) of the neuron
- believed to be strongly linked to memory (e.g. through addition of AMPA receptors to membrane)
- toxicity
- Ca2+ toxic at high neuronal cytosol concentrations (activation of proteases, phospholipases, free radicals)
- neurons, if exposed to low level [glutamate] for a few minutes, will die (partly due to NMDA receptors)
- excitotoxicity: destruction of neurons by excitatory neurotransmitters
- NMDA receptors mediate excitotoxicity due to ischemia
- brain ischemia: reduction in blood supply to the brain
- global ischemia: can result from cardiac arrest
- focal ischemia: can result from stroke
- excessive glutamate and Ca2+ influx as a result of ischemia
- reduction of blood supply lowers O2 levels in the brain, reducing ATP production
- Na+/K+ ATPase enzymes shut down, and membrane potential declines
- depolarization causes glutamate to be synaptically released, activating postsynaptic receptors
- excessive Ca2+ enters the cell, participating in cellular damage
- excessive glutamate from other conditions: protracted seizure
- clinical use: NMDA receptor antagonists
- receptor antagonists can block binding of glutamate, though hallucinations can result as a side effect
- phencyclidine (PCP): noncompetitive antagonist of NMDA receptors
GABA and glycine receptors
- GABAA, glycine receptors
- type: inhibitory
- distribution: both found throughout CNS, but are preferentially found in certain areas
- GABA: midbrain, cerebellum, cortex
- glycine: brainstem, spinal cord
- specificity: Cl-
- ECl: -75 mV
- kinetics: rapid
- inhibitory synapse localizaiton: soma, proximal dendrites
- excitatory: tend to distribute over distal dendrites
- inhibitory: tend to distribute over proximal dendrites, soma, and sometimes even the hillock
- acts as a current shunt that reduces AP
- enhanced inhibitory conductance reduces temporal and spatial summation in dendrites, soma
- GABAA-mediated inhibition stabilizes neuronal circuits
- brain: contains numerous excitatory loops that, unchecked, can lead to seizure
- inhibition stabilizes such circuitry by preventing uncontrolled excitability
- GABAA receptors, anesthesia, and sedation
- characteristics of general anesthesia
- analgesia (pain reduction)
- neuromuscular blockade
- hypnosis, amnesia, and unconsciousness
- reflex block
- almost all known general anesthetics act by enhancing GABAA receptor function
- general anesthetics: chloroform, ether, halothane, chloral hydrate, enthanol, pentobarbital, neurosteroids
- others: diazepam (Valium), midazolam (Versed), zolpidem (Ambien), flunitrazepam (Rohypnol)
- mechanism: allosteric regulation (bind at receptor/channel complex, at a different site)
- make ion channels respond more efficiently
- because of this, the channel is open for longer periods of time
- chloride conductance increases on average, giving more postsynaptic inhibition
- antagonists of GABAA and glycine: convulsions
- penicillin: channel blocker (similar to Mg2+ and NMDA); only potent in this way at high concentrations
- strychnine: competitive antagonist of glycine receptors
- general: blocking fast inhibitory transmission likely will result in convulsions or seizures
the nicotinic acetylcholine receptor (nAChR) of the brain
- nAChR receptor in the brain
- type: cation channel
- specificity: among other things, allow Ca2+ influx
- location: found on dendrites, presynaptic nerve terminals
- on activation, lets in enough Ca2+ to cause transmitter release, circumventing need for AP
- found notably on neurons involved in “reward responses” and dopamine release
- clinical: strongly implicated in addiction responses
- nicotine from a single cigarette can activate these receptors
- receptors can become desensitized over the course of the day, so cigarettes more potent early
neuromodulation
- slow synaptic transmission: indirect modulation of ion channels
- neuromodulation: response properties altered by activation of channels indirectly modulated by neurotransmitter
- duration: relatively respond more slowly, act for longer time
- effect: change the character of electrical activity, rather than directly eliciting responses
- spatial range: slow-acting action over a broad area
- ligand-gated: abrupt, point-to-point communication between neurons
- slow-acting: effects over a wide area
- receptors have high affinity for ligands, so can respond even at long distances to low concentrations
- problem: communication is extremely slow
- the mechanism of slow synaptic transmission
- transmitters: acetylcholine, glutamate, GABA, serotonin, norepinephrine
- fast-acting and slow-acting depends on receptor, rather than the transmitter
- thus glutamate and GABA are both fast-acting and slow acting
- metabotropic (slow-acting) receptors
- structure: single polypeptide with 7 transmembrane domains, external N-terminus
- mechanism: receptor binding activates a G-protein that induces formation of second messengers
second messengers modulate channels or kinases that also modulate channels
- function: alter functional properties of channels
- examples of neuronal modulation
- modulation: influence other processes in the cell, rather than directly participating in electrical propagation
- postsynaptic modulation: alteration of the response properties of a cell
- response properties: characteristic patterns of AP activity a neuron makes in response to stimuli
- example: norepinephrine and the hippocampus
- under normal conditions, these neurons will adapt to constant stimuli
- norepinephrine causes the neuron to no longer adapt, maintaining firing as long as stimulus is present
- increases cAMP, which activates PKA
- PKA phosphorylates Ca2+-activated K+ channels, reducing probability of opening
- change in excitability of one cell alters communications between many cells
- presynaptic modulation: alteration of the amount of neurotransmitter released
- presynaptic receptors (autoreceptors): receptors located in the presynaptic area
- example: metabotropic glutamate receptor (presynaptic receptor)
- activation via glutamate, ACPD (drug) causes a G protein to bind, directly inhibit opening of a Ca2+ channel
- less transmitter is released, so communication with postsynaptic cells is reduced
- if glutamate is the released neurotransmitter, this is an example of negative feedback
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