Chemical Signaling in the Nervous System

The adult brain averages 86 billion (∼10 ¹¹ ) neurons plus an equal number of nonneuronal support cells according to recent estimates. Each neuron can make thousands of terminal contacts, meaning that there are 10 ¹⁴ to 10 ¹⁵ connections within the brain, with still more in the periphery. We can bring some order to this massive system by understanding the chemistry used to coordinate specific neurotransmitters in conveying information and directing the body’s activity.

The Synapse: Adaptable to Many Tasks

The synapse is adaptable to many tasks. Controlled release of one or more small molecules is the keystone of nerve communication, and these small molecules are the nervous system’s neurotransmitters, typically stored in small synaptic vesicles that are released at synapses —specialized structures incorporating a presynaptic neuron and a postsynaptic target cell ( Fig. 4.1 ). The structure and function of individual synapses are customized according to the requirements of a particular task. The synapse must regulate the synthesis, storage, and release of one or more transmitters, and signal transduction must include one or more receptors at the target cell and a mechanism to terminate the signal. This chapter will discuss the individual classes of transmitters in some detail, using each to illustrate one or more of these six principal features of chemical transmission.

Fig. 4.1, Delivery of the chemical signal at a synapse. Synapses are the chemically and anatomically specialized sites where neurons deliver chemical signals to target cells ( left ). In the typical neuron to neuron synapse, anterograde axon transport delivers synaptic vesicles to the nerve terminals, where they advance to the active zones to be primed for release. When an action potential depolarizes the terminal, voltage-dependent calcium channels open, allowing calcium to enter. It is this calcium that triggers docking proteins to fuse the vesicle membrane to the plasma membrane, releasing the neurotransmitter into the synaptic cleft, where it binds to receptors on the target cell. The chemical signal is terminated when the neurotransmitter is transported back up into the nerve terminal for reuse or changed into an inactive metabolite by an enzyme on the postsynaptic membrane or in the synaptic cleft. The particular details of synaptic function differ greatly from one site to the next, and the glutamatergic synapse ( right ) diverges from the general schema in a variety of ways. For instance, multiple varieties of glutamate receptors (the AMPA, NMDA, KA ionotropic receptors, and three mGluR metabotropic receptors) are found on the target cell, on the presynaptic terminal and on neighboring astrocytes. Moreover, the cleft glutamate is not degraded enzymatically or returned to the neuron where it originated, but it is removed by transport proteins on the target cell (EAAT2) and surrounding astrocytes (EAAT1 and EAAT3) for later processing (see Fig. 4.5 ). AMPA, AMPA receptor; EAAT, excitatory amino acid transporter; KA, kainate receptor; mGluR, metabotropic glutamate receptor; NMDA, NMDA receptor.

Structure and Function

In many cases, neurotransmission occurs at a complex structure comprising the nerve terminal, a synaptic space, the postsynaptic cell, glia, and other supporting structures—the synapse. Individual cases show considerable variability: The synapse may occur anywhere along the neuron’s axon. While the postsynaptic element is generally a dendrite and an axon terminal is often the presynaptic element, neuron cell bodies, axons, and dendrites can all be presynaptic or postsynaptic in nature. Indeed, the synapse may release a hormone that acts at another location entirely. Regardless, in each case the elements are adapted to a specific purpose: to optimize transmitter storage, its release, its effects, and its disposition.

Transmitters and Modulators

The majority of vesicles in the nervous system contain one or the other of the common transmitters ( Table 4.1 ): glutamate, γ-aminobutyric acid (GABA), glycine, or acetylcholine. Most synapses also use modulators of synaptic activity whose release is tightly regulated, such as the biogenic amines ( dopamine, norepinephrine, or serotonin ) and the neuropeptides. Still others, such as nitric oxide and the endorphins, diffuse from the neuron as they are synthesized.

Table 4.1

Neurotransmitters

Class	Examples	Mimetics and Antagonists
Gas	NO, CO, H ₂ S	Nitroglycerine
Ion	Zn ²⁺ , Mg ²⁺ , Ca ²⁺
Cholinergic	Acetylcholine	Succinylcholine, curare, atropine, scopolamine
Monoamine	Epinephrine Norepinephrine	Yohimbine, propranolol, and many antipsychotic drugs
	Dopamine	l -DOPA, clonidine, amphetamine
	Serotonin	Ergotamine, LSD
	Histamine	Antihistamines
	Trace amine	Tyramine, β-phenylethylamine, amphetamine
Amino Acid	Glutamate
	GABA (γ-aminobutyric acid)	Benzodiazepine
	Glycine	Strychnine
Purine	Adenosine ATP (adenosine triphosphate)	Caffeine
Opioid	Enkephalin	Morphine
Eicosanoids	Leukotriene B ₄ , C ₄	Aspirin
Cannabinoid	2-Arachidonoylglycerol Anandamide	Tetrahydrocannabinol
Peptide	VIP (vasoactive intestinal polypeptide)
	Np-Y (neuropeptide-Y)
	Angiotensin

The soluble endogenous ligands of the nervous system can be grouped into nine classes of chemicals. Common examples are listed along with the more common naturally occurring therapeutic and toxic agonists or antagonists. A comprehensive source of information about ionotropic and metabotropic receptor proteins is found at http://www.guidetopharmacology.org .

CO, carbon monoxide; l -DOPA, l -3,4-dihydroxyphenylalanine; H ₂ S, hydrogen sulfide; LSD, lysergic acid diethylamide; NO, nitric oxide.

Synthesis and Storage

Most synapses synthesize multiple neurotransmitters from precursors that require specific transporters to cross the nerve’s plasma membrane and often the blood-brain barrier. Synthesis and storage in small synaptic vesicles is generally an ongoing process in the nerve terminal, supplemented by neurotransmitter and neurotransmitter precursors that are recycled from the synaptic cleft and neighboring astrocytes ( Fig. 4.1 ). Neurotransmitters are often stored together, often with one molecule as the counterion (adenosine triphosphate [ATP], glutamate) to another (acetylcholine, the biogenic amines), to neutralize electrical charges ( Fig. 4.2 ). Solute and primary active transporters are adapted to specific storage and uptake needs ( Table 4.2 ). Neuropeptides are a special case as they are synthesized in the soma and are stored in dense-cored vesicles (DCVs) that package the peptide with another major neurotransmitter.

Fig. 4.2, Filling the synaptic vesicle: norepinephrine as an example. Synaptic vesicles concentrate their neurotransmitters by electrical and proton gradients generated by the vacuolar-type H + ATPase ( V-ATPase ). Like the mitochondrial F 1 F o ATP synthase (but rotating in the opposite direction), V-ATPase catalyzes the active transport of protons into the vesicle via a rotating subunit powered by ATP hydrolysis. The V-ATPase protein has four components: a catalytic subunit that is attached to the actin cytoskeleton, a central stalk, a rotating subunit in the plane of the membrane’s bilayer and a peripheral stalk. Hydrolysis of ATP in the catalytic subunit turns the rotor in a clockwise direction at speeds of up to 10 3 rpm, importing protons through an H + channel between the peripheral stalk and the rotor. One complete rotation translocates three protons, one of which is consumed by a cycle of the CLC-5 2-chloride/1-proton countertransporter; the net result is a gain of two H + Cl − . This schema preserves microscopic electoneutrality, ultimately allowing the hydrogen ions to become 30-fold concentrated relative to the cytoplasm, a ΔpH of 1.5. Passive efflux of the chloride ion through the CLC-3 channel generates a diffusion membrane potential (Δψ), with the vesicle being inside 80-mV positive. The proton gradient drives countertransport uptake of dopamine, norepinephrine, serotonin, and acetylcholine by vesicular monoamine transporters such as VMAT. Uniquely among the small neurotransmitters, the final step of norepinephrine synthesis occurs within the synaptic vesicle, where dopamine β-hydroxylase adds a hydroxyl group to dopamine. The membrane potential drives uptake of the negatively charged neurotransmitters glutamate and ATP via organic anion transporters such as VGLUT. Thus, in this example, the synaptic vesicle will contain two neurotransmitters, the cation norepinephrine and the anion glutamate. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CLC, chloride channel; VGLUT, vesicular glutamate transporter; VMAT, vesicular monoamine transporter.

Table 4.2

Membrane Transport Proteins of the Synapse

Class of Transporter	Gene(s)	Protein(s)	Stoichiometry of Transported Substance(s)	Functional Purpose
Primary Active Transport
P-type Na ⁺ -K ⁺ ATPase	2 gene products	Dimer of dimers	3 Na ⁺ out/2 K ⁺ in per ATP	Establish sodium gradient
V-type H ⁺ ATPase	12 gene products	4 subunits, 23 proteins	2 H ⁺ in per ATP	Acidify cell organelles
Anion Channel/Pump Transporters
CLC transporters and channels	CLCN-3	CLC-3	Chloride ↑	C h l oride c hannel
CLC transporters and channels	CLCN-5	CLC-5	2 Chloride/proton ⇅	Vesicular chloride exchanger
Solute Carrier
MFS ( M ajor F acilitator S uperfamily) Clan
*Glu* cose t ransporters	SLC2A1	GLUT1	Glucose ↑	Transport of glucose across the blood brain barrier
	SLC2A3	GLUT3	Glucose ↑	High-affinity, non–insulin-dependent glucose transport into neurons
	SLC2A4	GLUT4	Glucose ↑	Insulin-dependent glucose transporter in fat and muscle
M ono c arboxylic acid t ransporter	SLC16A1	MCT1	H ⁺ and ketone body ⇈	Ferries ketone bodies across the blood-brain barrier
Organic anion transporters	SLC17A1, SLC17A2, SLC17A3	VGLUT1, 2 and 3	Glutamate ↑	Loads vesicles with glut amate
Organic anion transporters	SLC17A9	VNUT	ATP ↑	Loads vesicles with ATP
V esicular m onoamine t ransporters	SLC18A1 SLC18A2	VMAT1 VMAT2	Monoamine/proton ⇅	Loads vesicles with biogenic amines
V esicular m onoamine t ransporters	SLC18A3	VAChT	Acetylcholine/proton ⇅	Loads vesicles with A cetyl ch oline
Organic cation transporter	SLC22A3	EMT	Uncertain	E xtraneuronal m onoamine t ransporter
E quilibrative n ucleoside t ransporters	SLC29A1, SLC29A2	ENT	Nucleoside ↕	Reuptake of ATP
E quilibrative n ucleoside t ransporters	SLC29A4	PMAT	Monoamine ↕	P resynaptic reuptake of m ono a mines plus adenosine
APC ( A mino Acid P olyamine Organocation) Clan
High-affinity ch oline t ransporter	SLC5A7	ChT	Na ⁺ and choline ⇈	Choline uptake into nerve terminal
L arge neutral a mino acid t ransporter	SLC7A5/SLC3A2 dimer	LAT1	Phenylalanine/a.a. ⇅ tyrosine/a.a. ⇅ l -DOPA/a.a. ⇅	Transport of phenylalanine, tyrosine and l -DOPA across the blood-brain barrier
Na ⁺ -dependent n eutral a mino acid t ransporters	SLC38A1 SLC38A8	SNAT1 SNAT8	Na ⁺ and glutamine ⇈	“A” system uptake of glutamine into soma and dendrites
Na ⁺ -dependent n eutral a mino acid t ransporters	SLC38A3	SNAT3	Na ⁺ and glutamine ⇈ / proton ⇅	“N” system astrocyte release of glutamine
SDF ( S odium: D icarboxylate Symporter F amily) Clan
E xcitatory a mino a cid t ransporters	SLC1A1 SLC1A2	EAAT3 EAAT1	3Na ⁺ and H ⁺ and glutamate ⇈/K ⁺ ⇅	Astrocyte uptake of glutamate
E xcitatory a mino a cid t ransporters	SLC1A3	EAAT2	3Na ⁺ and H ⁺ and glutamate ⇈/K ⁺ ⇅	Postsynaptic uptake of glutamate
SNF ( S odium: N eurotransmitter Symporter F amily) Clan
Presynaptic catecholamine re-uptake transporters	SLC6A1	GAT1	3 Na ⁺ and Cl ⁻ and GABA ⁺ ⇈	Neuronal reuptake of GABA
	SLC6A2	DAT	2 Na ⁺ and Cl ⁻ and DA ⁺ ⇈	Neuronal reuptake of dopamine
	SLC6A3	NET	Na ⁺ and Cl ⁻ and NE ⁺ ⇈	Neuronal reuptake of norepinephrine
	SLC6A4	SERT	Na ⁺ and Cl ⁻ and 5-HT ⁺ ⇈	Neuronal reuptake of serotonin
	SLC6A5	GlyT2	3 Na ⁺ and Cl ⁻ and gly ⇈	High-affinity neuronal reuptake of glycine
	SLC6A9	GlyT1	2 Na ⁺ and Cl ⁻ and gly ⇈	Low-affinity buffering of glycine by astrocytes
	SLC6A11	GAT3	3 Na ⁺ and Cl ⁻ and GABA ⁺ ⇈	GABA uptake by astrocytes

Transport of small molecules is crucial to the process of chemical signaling. (1) Primary active transport concentrates sodium and hydrogen ions via hydrolysis of ATP. (2) CLC proteins transport chloride ions via pump or channel routes. (3) SLC proteins transport solutes according to the electrical and chemical gradients across cell and vesicular membranes. More 300 human SLC proteins in 46 gene families have been identified, many of which are central to neuron function. Phylogenetic studies of gene homologies have grouped these gene families into 23 superfamilies, 4 of which are important to the mechanisms discussed in this chapter. A comprehensive source of information about transport proteins is found at: http://www.guidetopharmacology.org .

⇅, Countertransport; ⇈, cotransport; ↑, unidirectional transport; ↕, equilibrative transport; a.a., amino acid; ACh, acetylcholine; ATP, adenosine triphosphate; CLC, chloride channel; CLCN, chloride voltage-gated channel; EMT, extraneuronal monoamine transporter; GABA, γ-aminobutyric acid; 5HT, serotonin or 5-hydroxytryptamine; SLC, solute carrier; SNAT, sodium-coupled neutral amino acid transporter; VAChT, vesicular acetylcholine transporter; VGLUT, vesicular glutamate transporter; VMAT, vesicular monoamine transporter; VNUT, vesicular nucleotide transporter.

Release

Release of the vesicle-stored transmitters is tightly regulated, with synapses able to release variable numbers of vesicles according to the strength of the signal to the nerve terminal. Vesicles themselves may open transiently, releasing only part of their contents, or they may fuse completely with the plasma membrane of the nerve. Some DCVs are released constitutively, and their transmitter’s release is controlled at the point of synthesis. Lipophilic neurotransmitters cannot be contained by vesicles, and so they are released as soon as they are made.

Transduction

All transmitters act by binding to some molecule, and that molecule is thus called its receptor. Occasionally, synapses consist of a single kind of transmitter acting on a single kind of receptor, resulting in a single kind of response, but most synapses contain multiple receptor types and use more than one transmitter. Receptors themselves can be simple, with a single binding site for the neurotransmitter and a single function, but most exhibit exuberant extracellular and intracellular structures that are the result of a wide variety of translational and posttranslational modifications and that are subject to allosteric modulation by metabolites, drugs, and chemical modifications. The response can be excitatory or inhibitory, depending on the receptor (but not the transmitter, because many transmitters can stimulate some processes and inhibit others, even at the same synapse). The responses can be divided into fast and slow processes, the fast synaptic responses being due to a change in the open or closed state of an ion channel (the ionotropic receptors) and the slow responses (the metabotropic receptors) being due to a change in the state of a G protein or some other enzyme ( Table 4.3 ).

Table 4.3

Receptors in the Nervous System

Class	Subfamily	Examples
A (19 subfamilies)	A17	Adrenergic receptors (α _{1A, 1B, 1D, 2A, 2B, 2C} and β _{1, 2, 3} ) Dopaminergic receptors (D _{1, 2, 3, 4, 5} ) Histaminergic receptor (H ₂ ) Serotonergic receptors (5-HT _{2A, 2B, 2C,6} )
	A18	Adenosine (previously P1) receptors (A _{1, 2a, 2b, 3} ) Histaminergic receptors (H _{1, 3, 4} ) Muscarinic cholinergic receptors (M _{1, 2, 3, 4, 5} )
	A11, A12	Purinergic receptors (P2Y _{1, 2, 4, 6, 8, 11, 12, 13} )
	A19	Serotonergic receptors (5-HT _{1A, 1B, 1D, 1E, 1F, 4, 5A, 7} )
	A4	Opioid receptors
	A13	Cannabinoid receptors
	A16	Cone pigments that transduce light
	Unclassified	Olfactory and vomeronasal receptors
B (3 subfamilies)	B1	Vasoactive intestinal peptide (VIP) receptor Calcitonin, glucagon, and secretin hormone receptors
C (5 subfamilies)	C2	GABA _B receptor
	C3	Glutamate receptor (mGluR _{1, 2, 3, 4, 5, 6, 7, 8} )
	C5	Taste receptors

All G protein–coupled (GPC) receptors contain seven transmembrane α helices. Approximately 800 genes in the human genome are predicted to be GPC member proteins, and they are divided into three classes, according to structural homology; each of the classes is further divided into numerous subfamilies whose members subsume a wide variety of functions throughout the body. Examples relevant to the nervous system are listed here, but a comprehensive source of information about G protein receptors is found at http://www.guidetopharmacology.org .

GABA, γ-aminobutyric acid; 5-HT, 5-hydroxytryptamine.

Termination

For much of the nervous system, any transmitter that is released by a nerve terminal is strictly limited to the immediate vicinity of the synapse, either by enzymatic digestion or by being recycled back into the presynaptic terminal. Transmitter that escapes the cleft is sequestered by solute transporters on the astrocytes or the postsynaptic cell or is removed by the cerebrospinal fluid or the vasculature ( Table 4.2 ). In the special case of neurohormones, release is designed to escape degradation because the target is distant.

Glutamate Receptors: The Tetrameric Excitatory Ionotropic Receptors

Glutamate is the neurotransmitter at 90% of the excitatory synapses in the brain. Six families of glutamate receptors exist in man: Three are ionotropic—the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), the kainate, and the NMDA ( N -methyl- d -aspartate) receptors, and three are metabotropic— group I, which increases inositol 1,4,5-trisphosphate (IP ₃ ) via G _q -coupled stimulation of phospholipase C and groups II and III, which decrease cyclic adenosine monophosphate (cAMP) via G _i /G _o -coupled inhibition of adenylyl cyclase. Glutamatergic synapses typically have ionotropic receptors on both the presynaptic and the postsynaptic membrane, with metabotropic receptors off to the side plus accessory proteins that anchor the receptors and modify their activation and permeability ( Fig. 4.1 ). The synaptic glutamate is recovered via the glutamate/glutamine cycle. First, glutamate is removed from the synaptic cleft by transport into surrounding astrocyte (via EAAT1 and EAAT2 [see Fig. 4.5B later]; all transporter acronyms are explained in Table 4.2 ) or into the postsynaptic neuron (via EAAT3), where glutamine synthase generates glutamine, incidentally consuming potentially toxic ammonia. This synaptically inert glutamine is recycled back into the cleft by an electroneutral Na ⁺ /H ⁺ countertransporter (SNAT3). Glutamine uptake by the glutamatergic nerve is by Na ⁺ cotransport (via SNAT8), followed by glutamate synthesis via phosphate-activated glutaminase. Vesicle uptake of this anionic neurotransmitter is by the vesicular glutamate transporter (VGLUT), driven by the interior-positive electrical gradient ( Fig. 4.2 ).

AMPA Receptors and Milliseconds of Excitation

AMPA and kainate receptors are the most common of the ionotropic glutamate receptors and open only briefly (for milliseconds) before they become desensitized. AMPA receptors (with four possible subunits, GluA1 to GluA4) and kainate receptors (with five possible subunits, GluK1 to GluK5) have a similar structure and function.

AMPA receptors are large—twice the size of the nicotinic receptors and four times the size of the glutamate metabotropic receptors ( Fig. 4.3 ). The outermost extracellular portion is the N ( a mino)- t erminal d omain ( ATD or NTD ), and the portion nearest the membrane is the l igand b inding d omain ( LBD ), with the t rans m embrane d omain ( TMD ) containing a box-like selectivity filter and gating apparatus. The AMPA ion pore is a highly conserved structure, present in potassium channels throughout the tree of life, from bacteria (the Streptomyces KcsA channel) to man (the K _v 11.1 ether-a-go-go channels, one of which repolarizes the cardiac action potential). If the GluA2 subunit is present, which is the usual case, the channel is permeable to sodium and potassium ions only. RNA editing causes the transcribed sequence for glutamine at codon 586 to be translated as an arginine in GluA2. This arginine adds an additional positive charge to the selectivity filter of the ion pore, thus excluding divalent cations such as calcium. Codon 586 is not A→I RNA edited in the other subunits, and so any AMPA receptor made without GluA2 is permeant to calcium. These calcium-permeant AMPA channels have a conductance that declines as the membrane is depolarized (an inward rectification) due to block of the ion pore by endogenous cytoplasmic polyamines. This inward rectification is of some benefit for a calcium permeant channel because it will lessen the quantity of calcium that enters the cell, reducing the toxic effects of a high cell calcium and minimizing the energy required to pump the calcium back out.

Fig. 4.3, The glutamate ionotropic receptor. The homotetrameric GluA2 AMPA receptor is shown as viewed from the front ( left ) and from the side ( right ). AMPA receptors have four subunits that associate as pairs of dimers, making a lentoid extracellular component that is wider than deep in this N assembly; heterotetramers can also exist as an O assembly, which is more compact. The outermost portion of the receptor is the N-( a mino) t erminal d omain ( ATD or NTD ) and the portion nearest the membrane is the l igand b inding d omain ( LBD, separated by the thin line ). The ATD is a pair of dimers, as the t rans m embrane d omain ( TMD ), but with partners swapped. That is to say, for a receptor made up with two GluA2s, one GluA1 and one GluA3, the ATD might pair a GluA2-GluA1 dimer with a GluA2∗-GluA3 dimer, but then the LBD would pair GluA2-GluA3 with GluA2∗-GluA1, thus tightly binding the heterotetramer into a functional whole. This twofold symmetry transforms into a fourfold symmetry at the TMD (the width of the cell membrane marked in gray ) to contain the box-like selectivity filter and gating apparatus. The TMD houses the pore, whereas the extracellular domain contains the ligand binding site. The NMDA ATD domain is larger and more compact, rendering it more oblate than lentoid. As a consequence, more of its sequence is in contact with the other GluN subunits and the LBD domain, which leads to more control of the receptor function. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N -methyl- d -aspartate.

Agonists bind to a clamshell slot in the LBD, which then snaps shut behind. With two glutamates bound, the channel begins to flicker brief openings. When a third glutamate binds, the channel opens for longer, giving more current, and with a fourth glutamate, the channel is open most of the time with still more current flowing. However, within seconds, the receptor becomes desensitized as dimers separate in the LBD and channel activity ceases.

The duration of the glutamate response at the AMPA receptor can be prolonged in a variety of ways. Alternative splicing occurs in a TMD exon, leading to slower AMPA closing in the fetal form than the adult variant. Phosphorylation of two serines by protein kinase C (PKC) and another by protein kinase A (PKA) increases and prolongs the glutamate response. T ransmembrane A MPA r eceptor p roteins (TARPs) modify the lifetime of the glutamate response by binding to the TMD. For instance, stargazin increases the rate of channel opening and slows desensitization.

NMDA Receptors and Seconds of Activation

NMDA receptors open to allow a large influx of calcium, but only after the receptor’s cell has been depolarized repeatedly over a period of hundreds of milliseconds. This calcium modulates many and varied cell processes by activating Ca ²⁺ /calmodulin-dependent kinases, protein kinase C, phospholipase C and A ₂ , calcineurin, and nitric oxide synthase. In cases of large, prolonged NMDA stimuli, this calcium signal is great enough to damage the cell and even be fatal. Functionally, the duration and amplitude of the NMDA response is modulated by many ions, by endogenous molecules, and by psychotropic drugs. It has been tentatively implicated in Alzheimer and Parkinson diseases, depression, schizophrenia, and ischemic neuron death after a stroke.

NMDA receptors are obligate heterodimers, requiring a pair of GluN1 to GluN2 dimers. There is only one gene encoding GluN1 (GRIN1), but it is alternatively spliced into eight variants. Four GluN2 monomers subtypes exist, and they are distributed with regional specificity throughout the brain. All monomers bind one glutamate, but only after the two GluN1s have bound a different ligand: d -serine. Glia synthesize d -serine (one of the only two d -amino acids to be used by vertebrates) from l -serine via serine racemase and release it into the synaptic area. Glycine, the inhibitory neurotransmitter of the brainstem and spinal cord, can substitute for d -serine.

The ATD of the NMDA (but not AMPA or kainate) receptor senses its surroundings’ pH, opening less frequently and for briefer periods as the receptor’s extracellular surroundings are made more acidic, potentially protecting the brain during periods of ischemic acidosis. Polyamines inhibit this effect. Little sequence homology is shared between the NMDA and AMPA/kainate ATDs.

The requirement that a cell be depolarized for an extended period of time before its NMDA receptors appear to open is explained by the presence of twin asparagines at the selectivity filter of the NMDA (but not the AMPA/kainate receptor) channel. Extracellular magnesium binds to the electronegative oxygens of these twin asparagines and is released only slowly when the membrane is depolarized from rest, a change in voltage that provides the electrical force to drive the divalent ion out of the channel. Thus the NMDA receptor will allow no current to pass even when activated by agonist at the resting potential because it is blocked by a magnesium ion. It is only with repeated glutamate stimuli acting on neighboring AMPA receptors that the membrane potential is near zero for long enough for blocking magnesium ion to exit the pore, allowing measurable currents to flow through a channel that was otherwise open the whole time. Limiting calcium entry is particularly important in the case of the NMDA receptor, both because its calcium currents are large when the magnesium block is finally relieved, but also because the receptors are often found in the membrane of dendritic spines, where the volume of the terminal bud is small and the cytoplasm is separated from the nerve cell body by a narrow stalk that restricts diffusion into and out of the spine. In these spines, any calcium entry will have a disproportionately large effect.

Kainate Receptors: AMPA-like, but Presynaptic

The kainate receptors are predominantly, but not exclusively, presynaptic. Sharing the structure and function of AMPA receptors, kainate receptors are generally permeant only to sodium and potassium because RNA editing has resulted in the glutamine→arginine substitution at codon 586, but may be calcium permeant because this editing is not obligatory. The calcium permeant kainate receptors augment transmitter release, but activating calcium impermeant receptors may result in a prolonged depolarization that is inhibitory at certain synapses and excitatory at others.

Five kainate monomers exist that can combine as homotetramers or heterotetramers. GluK1, GluK2, and GluK3 combine to form channels, whereas GluK4 and GluK5 do not, merely being able to modify the function of the heterotetramer they participate in. The structure of the kainate receptor’s LBD allows domoic acid to bind tightly to the ligand site, causing a prolonged activation. This toxin is produced by a red algae, and it is concentrated by mollusks during a bloom of that algae, resulting in sporadic cases of the amnestic shellfish poisoning syndrome. Eating tainted shellfish can result in neurotoxic levels of calcium influx through kainate receptors in the hippocampus and amygdala.

Cys-Loop Receptors: The Pentameric Multifunctional Ionotropic Receptors

Cys-loop receptors are pentamers of four or five different monomers that might have acetylcholine, GABA, glycine or serotonin as its agonist. The structure and function of the nicotinic acetylcholine receptor ( nAChR ) was discussed at length in Chapter 3 . This section will present details about the structure of the synapse, about how the transmitter is stored and released, how failures in synaptic function occur, and, finally, how other transmitters use this receptor type.

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