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Cellular Signaling 

Cellular Signaling
Chapter:
Cellular Signaling
Author(s):

Nathan P. Staff

DOI:
10.1093/med/9780190214883.003.0024
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Overview

Cell communication in the nervous system is finely tuned to respond rapidly to external stimuli, learn from those stimuli, and produce more effective responses in the future. The physical basis for this cell communication is the manipulation of ion gradients via ion pumps and channels, chemical neurotransmission, and synaptic plasticity, all of which are discussed in this chapter.

Neuronal Excitability

The majority of cell communication that occurs in the nervous system relies on maintenance of a transmembrane electrochemical potential, which at rest is approximately −70 mV. This transmembrane potential is primarily developed by the action of the sodium-potassium-adenosine triphosphatase transport that shuttles 3 sodium ions out of the cell while bringing 2 potassium ions into the cell. Four main ions have electrochemical gradients across the plasma membrane and contribute substantially to neuronal excitability, and each ion acts independently to achieve equilibrium, according to the Nernst equation. These ions (and their approximate equilibrium potentials) are sodium (0 mV), potassium (−75 mV), calcium (+20 mV), and chloride (−90 mV). Thus, when a selective ion channel (eg, sodium) is opened under resting conditions (−70 mV), the transmembrane potential rapidly moves toward the equilibrium potential of that channel (eg, +20 mV).

Ion channels are transmembrane proteins that have a selectivity pore for specific ions. Most ion channels are not constitutively open and are thus gated by an external mechanism, which in most cases is from either a change in transmembrane voltage (voltage-gated ion channels) or binding of a chemical neurotransmitter or second messenger cascade (ligand-gated ion channels). Additionally, once the external force opens a given ion channel, it likely has a mechanism to transition into an inactivated state shortly thereafter. The classic voltage-gated ion channel is the fast-activating, fast-inactivating voltage-gated sodium channel. When the transmembrane potential becomes more positive (depolarization) from the resting potential, the voltage-gated sodium channel is more likely to be in the open or activated state. This leads to more depolarization via sodium flow through the channel toward its equilibrium potential. As the membrane becomes more depolarized, a second independent process takes place within the voltage-gated ion channel wherein a portion of the channel gains access to a binding site within the ion pore that effectively plugs the pore, thus inactivating the channel.

The voltage-gated sodium channel is the key determinant of the nerve action potential, which is an all-or-none phenomenon that occurs within the axon and propagates along the axon to its target. The depolarizing phase of the action potential is driven by the voltage-gated sodium channel (Figure 24.1). As the membrane potential becomes depolarized, delayed activation of voltage-gated potassium channels helps the potential become more negative (hyperpolarization), moving it toward the potassium equilibrium potential (−75 mV).

Figure 24.1 Ionic Basis of the Action Potential in Axons.
Action potentials occur as a result of opening and closing of specific voltage-gated ion channels. The depolarizing upstroke of the action potential is mediated by a voltage-gated sodium (Na+) channel that has a fast activation, allowing the membrane potential to approach the equilibrium potential (E) for sodium (ENa+). The voltage-gated sodium channel has fast inactivation (NaV). The repolarization is then mediated by a voltage-gated potassium (K+) channel (delayed rectifying potassium channel; KV1) that brings the membrane potential toward the equilibrium potential for potassium (EK+). AHP indicates afterhyperpolarization; I, current.

Figure 24.1 Ionic Basis of the Action Potential in Axons.

Action potentials occur as a result of opening and closing of specific voltage-gated ion channels. The depolarizing upstroke of the action potential is mediated by a voltage-gated sodium (Na+) channel that has a fast activation, allowing the membrane potential to approach the equilibrium potential (E) for sodium (ENa+). The voltage-gated sodium channel has fast inactivation (NaV). The repolarization is then mediated by a voltage-gated potassium (K+) channel (delayed rectifying potassium channel; KV1) that brings the membrane potential toward the equilibrium potential for potassium (EK+). AHP indicates afterhyperpolarization; I, current.

The speed of action potential propagation along an axon is determined by several factors: axonal diameter (larger is faster), temperature (warmer is faster), and myelination. In the peripheral nervous system, there are both myelinated and small unmyelinated axons. Large myelinated axons have conduction velocities of about 60 m/s, whereas small unmyelinated axons have conduction velocities of approximately 2 m/s. Myelination leads to a much faster conduction velocity due to saltatory conduction than can be achieved by increasing axonal diameter. Myelination (by either Schwann cells in the peripheral nervous system or oligodendrocytes in the central nervous system) forms an insulating wrap along a segment of axon (internode); between regions of myelination, there is a small region (the node of Ranvier) that does not contain myelin and is highly enriched for the voltage-gated sodium and potassium channels that underlie the action potential (see Figure 25.1 in Chapter 25). In saltatory conduction, the action potentials effectively skip along the nodes, quickly propagating to their intended target.

Many varieties of voltage-gated ion channels are distributed along neuronal axons, somata, and dendrites in a cell-specific manner. Because each voltage-gated ion channel has a unique pattern of activation and inactivation, and depending on a channel’s placement within a given neuron (which may have one of many different morphologies), there exists a bewildering array of neuronal phenotypes that are specialized for their given tasks. There are 10 types of voltage-gated sodium channels (Nav1-9 and Navx), many of which are blocked by the pufferfish toxin (ie, tetrodotoxin) or local anesthetics (eg, lidocaine). Potassium channels come in many varieties, some of which are voltage gated, calcium activated (typically activating after extensive neuronal firing), or second messenger gated. Voltage-gated calcium channels are distributed throughout the nervous system. Some types are involved in the burst firing of action potentials, in pacemaker properties, and in the presynaptic terminal (P/Q type) where they are critical for chemical neurotransmission.

Chemical Neurotransmission

Cell communication in the central nervous system (and neuromuscular junction) occurs primarily at synaptic terminals and is mediated by chemical neurotransmission. As the action potential enters the presynaptic terminal, voltage-gated calcium channels (P/Q type) are activated, allowing calcium ions to enter the neuron. In the majority of neurons, entry of calcium ions leads to a cascade of events that causes a neurotransmitter-filled synaptic vesicle to fuse with the plasma membrane, thus releasing its neurotransmitter into the region between the presynaptic and postsynaptic neuron (ie, the synaptic cleft). The neurotransmitter then diffuses across the synaptic cleft and binds to postsynaptic receptors. These postsynaptic receptors are often ligand-gated ion channels, which then open and either depolarize (excitatory effect) or hyperpolarize (inhibitory effect) the postsynaptic neuron. Mechanisms exist to remove the neurotransmitter from the synaptic cleft by either hydrolyzing the neurotransmitter in the cleft (ie, acetylcholinesterase) or pumping the neurotransmitter into either the presynaptic terminal or the glia, which then completes the cycle of chemical neurotransmission in neuronal communication.

The presynaptic terminal is a complex and highly regulated structure within the neuron. Synaptic vesicles are filled with the neurotransmitter and then eventually are docked along the plasma membrane by a series of specialized synaptic proteins. Toxins target several synaptic proteins. Botulinum toxin targets synaptobrevin, synaptosomal-associated protein 25 (SNAP-25), and syntaxin in the neuromuscular and autonomic presynaptic terminals, whereas tetanus toxins target synaptobrevin in the central inhibitory presynaptic terminals.

Key Peripheral Nervous System Neurotransmitter System: Neuromuscular Junction

Alpha motor neurons in the anterior horn of the spinal cord innervate skeletal muscle and use acetylcholine as their neurotransmitter. The presynaptic terminal releases acetylcholine as described above (Figure 24.2). Acetylcholine diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors, which then open a nonselective cation channel that depolarizes the muscle membrane. The depolarizing wave across the muscle membrane enters T tubules and activates a voltage-gated calcium channel that causes calcium influx and muscle contraction via the interaction of troponin, tropomyosin, actin, and myosin. Acetylcholinesterase (inhibited by pyridostigmine) resides in the synaptic cleft and hydrolyzes acetylcholine to inactivate it.

Figure 24.2 General Organization of the Neuromuscular Junction.
The neuromuscular junction comprises the presynaptic motor nerve terminal, the postsynaptic myocyte structures, and an enveloping Schwann cell. In the presynaptic terminal, synaptic vesicles are filled with acetylcholine (ACh) and prepared by exocytosis, which is dependent on activation of closely aligned voltage-gated calcium channels (VGCCs). Postsynaptically, the myocyte has ultrastructural organization that increases the surface area via junctional folds that are studded with nicotinic acetylcholine receptors (nAChRs). Acetylcholinesterase (AChE) fills the synaptic cleft and rapidly degrades ACh within the cleft, ensuring a rapid, nonsustained response. Nav1.4 indicates voltage-gated sodium channel 1.4.

Figure 24.2 General Organization of the Neuromuscular Junction.

The neuromuscular junction comprises the presynaptic motor nerve terminal, the postsynaptic myocyte structures, and an enveloping Schwann cell. In the presynaptic terminal, synaptic vesicles are filled with acetylcholine (ACh) and prepared by exocytosis, which is dependent on activation of closely aligned voltage-gated calcium channels (VGCCs). Postsynaptically, the myocyte has ultrastructural organization that increases the surface area via junctional folds that are studded with nicotinic acetylcholine receptors (nAChRs). Acetylcholinesterase (AChE) fills the synaptic cleft and rapidly degrades ACh within the cleft, ensuring a rapid, nonsustained response. Nav1.4 indicates voltage-gated sodium channel 1.4.

(Used with permission of Mayo Foundation for Medical Education and Research.)

Various myasthenic syndromes help illustrate the function of the neuromuscular junction. In autoimmune myasthenia gravis, autoantibodies may target either the acetylcholine receptor or a closely associated muscle-specific kinase. In Lambert-Eaton myasthenic syndrome, autoantibodies target the presynaptic P/Q voltage-gated calcium channel, thus hampering adequate presynaptic calcium levels for exocytosis. Many forms of congenital myasthenic syndromes are caused by mutations in various components of the neuromuscular junction, including the acetylcholine receptor, acetylcholinesterase, and choline acetyltransferase (protein that pumps acetylcholine into synaptic vesicles).

Key Central Nervous System Neurotransmitter Systems: Glutamate and [γ‎]-Aminobutyric Acid

Postsynaptic receptors for neurotransmitters are often categorized as excitatory (causing depolarization), inhibitory (causing hyperpolarization), or neuromodulatory (causing slow changes in potentials or provoking second messenger cascades). The most ubiquitous excitatory neurotransmitter is glutamate (produced by metabolism of glutamic acid), which is mediated through α‎-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) and N-methyl- d-aspartate (NMDA) receptors (Figure 24.3). The AMPA receptor is a ligand-gated ion channel that binds glutamate and opens a sodium-predominant cation channel whose equilibrium potential is near 0 mV. This is the main receptor responsible for fast excitatory neurotransmission in the brain. The NMDA-type glutamate receptor has properties that implicate it as a major mediator of neuronal plasticity (and presumably learning and memory). The NMDA receptor requires glutamate binding for activation and concomitant depolarization to achieve its full effect. This binding is necessary because, at normal resting membrane potential, there is a magnesium ion in the pore that is released on depolarization and results in calcium influx into the postsynaptic terminal. This local influx of calcium can lead to synapse-specific changes in the postsynaptic neuron that are considered to be the cellular basis for learning and memory.

Figure 24.3 General Organization of the Glutamatergic Synapse in the Central Nervous System.
The central nervous system glutamatergic synapses comprise a presynaptic glutamatergic axonal nerve terminal, a postsynaptic dendritic spine, and an enveloping astrocytic process. Glutamate is formed from glutamine and packaged into synaptic vesicles that are released via exocytosis in a calcium-dependent fashion. The postsynaptic dendritic spine contains 3 main glutamate receptors, the α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the N-methyl-d-aspartate receptor (NMDAR), and the metabotropic glutamate receptor (mGluR). When fully activated, the postsynaptic spine depolarizes and has increased intracellular calcium, a signal involved in synaptic plasticity. Glutamate is taken up by excitatory amino acid transporters (EAATs) to ensure efficient neurotransmission and prevent excitotoxicity. Ca2+ indicates calcium ion; EPSP, excitatory postsynaptic potential; Gq, Gq protein; IP, inositol phosphate; Na+, sodium ion; NH3, ammonia; PiP, phosphatidylinositol phosphate; PLC, phospholipase C.

Figure 24.3 General Organization of the Glutamatergic Synapse in the Central Nervous System.

The central nervous system glutamatergic synapses comprise a presynaptic glutamatergic axonal nerve terminal, a postsynaptic dendritic spine, and an enveloping astrocytic process. Glutamate is formed from glutamine and packaged into synaptic vesicles that are released via exocytosis in a calcium-dependent fashion. The postsynaptic dendritic spine contains 3 main glutamate receptors, the α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the N-methyl-d-aspartate receptor (NMDAR), and the metabotropic glutamate receptor (mGluR). When fully activated, the postsynaptic spine depolarizes and has increased intracellular calcium, a signal involved in synaptic plasticity. Glutamate is taken up by excitatory amino acid transporters (EAATs) to ensure efficient neurotransmission and prevent excitotoxicity. Ca2+ indicates calcium ion; EPSP, excitatory postsynaptic potential; Gq, Gq protein; IP, inositol phosphate; Na+, sodium ion; NH3, ammonia; PiP, phosphatidylinositol phosphate; PLC, phospholipase C.

(Used with permission of Mayo Foundation for Medical Education and Research.)

γ‎-Aminobutyric acid (GABA) is the main mediator of inhibitory neurotransmission in the brain. It is produced by decarboxylation of l-glutamate by glutamic acid decarboxylase; antibodies against this enzyme are associated with stiff person syndrome. There are 2 main types of GABA receptors: type A (GABAA) and type B (GABAB). GABAA receptors mediate fast inhibitory neurotransmission by means of a ligand-gated chloride channel mechanism and are the target of benzodiazepines, barbiturates, and ethanol. GABAB receptors mediate inhibitory neurotransmission but have slower kinetics because they work by means of a second messenger cascade that activates a potassium channel.

The vast neuromodulatory neurotransmitter system is distributed throughout the central nervous system, and the key points are listed in Table 24.1.

  • The voltage-gated sodium channel is the key determinant of the nerve action potential, which is an all-or-none phenomenon that occurs within the axon and propagates along the axon to its target.

  • The speed of action potential propagation along an axon is determined by several factors: axonal diameter (larger is faster), temperature (warmer is faster), and myelination.

  • Postsynaptic receptors are often ligand-gated ion channels, which open and either depolarize (excitatory effect) or hyperpolarize (inhibitory effect) the postsynaptic neuron.

  • Botulinum toxin targets synaptobrevin, SNAP-25, and syntaxin in the neuromuscular and autonomic presynaptic terminals, whereas tetanus toxins target synaptobrevin in the central inhibitory presynaptic terminals.

  • Alpha motor neurons in the anterior horn of the spinal cord innervate skeletal muscle and use acetylcholine as their neurotransmitter.

  • The most ubiquitous excitatory neurotransmitter is glutamate (produced by metabolism of glutamic acid), which is mediated through AMPA and NMDA receptors.

  • GABA is the main mediator of inhibitory neurotransmission in the brain.

Table 24.1 Neurotransmitters in the Central Nervous System

Neurotransmitter

Receptors

Receptor Type

Anatomical Cell Body Distribution

Anatomical Receptor Distribution

Key Points

Clinically Relevant Pharmacology or Toxicologya

Glutamate

AMPA

Excitatory

Ubiquitous CNS

Ubiquitous CNS

Primary mediator of fast excitatory neurotransmission

NMDA

Excitatory

Ubiquitous CNS

Ubiquitous CNS

Critical for synaptic plasticity

Memantine (–)

Metabotropic

Neuromodulatory

Ubiquitous CNS

Ubiquitous CNS

Autoimmune NMDAR encephalitis

GABA

GABAA

Inhibitory (fast kinetics)

Ubiquitous CNS

Ubiquitous CNS

Primary mediator of fast inhibitory neurotransmission

Benzodiazepines (+)

Barbiturates (+)

Volatile anesthetics (+)

Ethanol (+)

Baclofen (+)

GABAB

Inhibitory (slow kinetics)

Ubiquitous CNS

Ubiquitous CNS

Glycine

Glycine

Inhibitory

Brain stem and spinal cord

Brain stem and spinal cord

Strychnine (–)

Acetylcholine

Nicotinic

Excitatory (M1)

Spinal motor neuron, spinal sympathetic neurons

Neuromuscular junction, autonomic ganglia

Pyridostigmine and donepezil (increase ACh via reduced degradation)

CNS (basal forebrain, mesopontine tegmentum)

Ubiquitous CNS

Succinylcholine (–)

Vecuronium (–)

Muscarinic

Excitatory

Autonomic ganglia

Parasympathetic targets

Excess causes much of cholinergic toxidrome

Pyridostigmine and donepezil (increase ACh via reduced degradation)

Inhibitory (M2)

CNS (basal forebrain, mesopontine tegmentum)

Ubiquitous CNS

Pilocarpine (+)

Atropine (–)

Scopolamine (–)

Dopamine

D1 type (D1 and D5)

Neuromodulatory (excitatory)

SNc

Caudate and putamen (SNc) nucleus accumbens, amygdala, hippocampus, prefrontal cortex (VTA)

Deficient in Parkinson disease;

Levodopa (+)

Dopamine agonists (eg, pramipexole) (+)

D2 type (D2, D3, D4)

Neuromodulatory (inhibitory)

VTA

Important role in reward system

Antipsychotics (eg, quetiapine) (–)

Serotonin

5-HT1

Neuromodulatory (inhibitory)

Raphe nuclei

Ubiquitous

Mood regulation (SSRI effect); sleep-wake cycle

Buspirone (+)

Triptans (+)

5-HT2

Neuromodulatory (excitatory)

Trazodone (–)

5-HT3

Excitatory

Ondansetron (–)

Histamine

H1

Neuromodulatory (excitatory)

Tuberomammillary nucleus of hypothalamus

Ubiquitous

Important in states of arousal; sleep-wake cycle

Sedating antihistamines

H2

Neuromodulatory (excitatory)

Amitriptyline (–)

H3

Neuromodulatory (inhibitory)

Norepinephrine

α‎1

Neuromodulatory (excitatory)

Locus ceruleus; lateral tegmental system

Ubiquitous

Important in states of arousal; sleep-wake cycle

Norepinephrine reuptake blocked by amphetamine/cocaine

Prazosin (–)

Amitriptyline (–)

α‎2

Neuromodulatory (inhibitory)

Clonidine (+)

Mirtazapine (–)

β‎

Neuromodulatory (variable)

Propranolol (–)

Abbreviations: ACh, acetylcholine; AMPA, α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNS, central nervous system; GABA, γ‎-aminobutyric acid; 5-HT1, 5-hydroxytryptamine receptor 1; 5-HT2, 5-hydroxytryptamine receptor 2; 5-HT3, 5-hydroxytryptamine receptor 3; NMDA, N-methyl-d-aspartate; NMDAR, N-methyl-d-aspartate receptor; SNc, sustantia nigra pars compacta; SSRI, selective serotonin reuptake inhibitor; VTA, ventral tegmental area.

a Minus sign indicates inhibitory at this receptor; plus sign, excitatory at this receptor.

Notes:

Abbreviations: AMPA, α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, γ‎-aminobutyric acid; NMDA, N-methyl-d- aspartate; SNAP-25, synaptosomal-associated protein 25