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Fast synaptic transmission is crucial for real-time functioning of the brain. All the receptor molecules that mediate fast transmission events are also ligand-gated ion channels, i.e., they are ion channels that undergo allosteric structural changes on binding a particular neurotransmitter molecule, resulting in the opening of the channel, the entry of selected ions into the neuron and subsequent signalling events. Their primary function is to receive signal input at postsynaptic membranes, where some also play central roles in synaptic plasticity. However, they are also found in postsynaptic membranes outside synapses, and in presynaptic terminals, where they are involved in the control of transmitter release. This chapter presents an overview of current knowledge of the molecular biology of these receptors.

G protein-coupled receptors (GPCRs) transduce extracellular signals into a multitude of intracellular changes including changes in electrical activity, levels of second messengers, secretion, morphology, growth, and differentiation. Understanding how the common structural features of these receptors allow such controlled yet complex signalling patterns is a fundamental question in neurobiology. This chapter discusses the overall structural features, receptor-ligand interactions, receptor-G protein interactions, and regulation of G protein-coupled receptor function.

This chapter focuses on the first two elements of the group: oxygen and sulfur. There is a section each on dioxygen and ozone, oxygen and dioxygen coordination compounds, and structure of water and ices (including protonated water species). For sulfur, coverage includes its allotropes and polyatomic sulfur species, metal complexes with sulfide anions as ligands, and oxides and oxoacids of sulfur. Finally, there is a section on the allotropes and stereochemistry of selenium and tellurium, as well as the polyatomic anions and cations of these elements.

Ionotropic glutamate receptors (iGluRs) are the principal mediators of fast excitatory transmission in the central nervous system. These receptors were originally distinguished by their specific binding of and responses to agonists such as N-methyl-D-aspartate (NMDA), quisqualate/α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA), and kainate, thus defining three subfamilies. More recent molecular biological studies have basically confirmed that the principal receptor types fall into these three main classes on the basis of similarities in amino acid sequence, but they also have indicated that each subfamily comprises more than one gene and, as a result of posttranscriptional modifications, many more receptor protein subunits. In addition, researchers have identified a further subgroup in vertebrates (the orphan δ receptors, δ1 and δ2) and another subfamily, the kainate binding proteins, in non-mammalian vertebrates. This chapter discusses the general characteristics of ionotropic glutamate receptors, posttranscriptional modifications, alternative splicing, RNA editing, ligand-binding site of iGluRs, mechanism of channel gating of iGluRs, and the ion channel and carboxyl-terminal domain of glutamate receptors.

This chapter discusses the detection and properties of electronic Na⁺−K⁺ transport in the squid axon membrane. The Na pump in the plasma membrane of animal cells mediates uphill transport of Na⁺ and K⁺. A number of investigators have sought experimental evidence for the Na/K pumping rate as a function of the membrane potential in a variety of cells and tissues. The occlusion of Na⁺ at the external surface is enhanced greatly with the decrease of external Na⁺ concentration and that occlusion of K⁺ is also greatly enhanced with the decrease of external K⁺ concentration. This seems to be a primary condition for the enzyme to pump in or pump out the ligand. The enzyme seems to be so designed as to adjust its structure for the change in ligand concentration and to continue its pumping function, even though its i _p -V characteristic shifts along the voltage axis. Changes of rate constants in the two state model with external K⁺ and Na⁺ concentrations are described in the chapter. If a similar mechanism is involved at the inner surface of the enzyme, changes of rate constants with internal K⁺ and Na⁺ concentrations can be anticipated. What can be expected with a decrease of internal Na⁺ concentration are a great increase of r ₂₁, almost no change of r ₁₂, decrease of k ⁰ ₁₂ and an increase of k ⁰ ₂₁. On the other hand, what can be expected with a decrease of internal K⁺ concentration are a great increase of r ₁₂, almost no change of r ₂₁, a decrease of k ⁰ ₁₂ and a great decrease of k ⁰ ₂₁. However, these remain to be proved.

NMDA receptors have a rich and diverse pharmacology reflecting the presence of multiple ligand binding sites at which agonists, antagonists, and modulators interact in an allosteric manner. This chapter describes concentration jump experiments used to characterize the activation of NMDA receptors by agonists and the block of NMDA receptor activity by competitive antagonists. These results were obtained before cDNAs for multiple families of NMDA receptor subunits were identified, and although the experiments illustrate important principles which would be expected to apply to all subtypes of NMDA receptor, a challenging task for the future will be to characterize in detail the ligand binding characteristics of native NMDA receptor subtypes in different areas of the brain.

This chapter compares the anatomical and pharmacological properties of the recombinant NMDA receptor subunits with the properties of native NMDA receptor subtypes. It first summarizes the anatomical distribution of individual receptor subunits and then compares their distributions with those of NMDA receptor subtypes identified in radio ligand binding studies. Radioligand binding studies indicate the presence of at least four pharmacologically distinct populations of NMDA receptors with differing regional distributions. There is substantial regional variation among members of both the NR1 and NR2 subunit families; however, the distributions of the NR2 subunits correspond much more closely to the distributions of the pharmacologically distinct NMDA receptor populations.

Ion channels are cellular proteins that conduct the movement of ions from one side of a membrane to the other. The resultant changes in local ion concentrations and electrical field play pivotal roles in physiological processes, as wide ranging as cell to cell communication, cell proliferation and secretion. This chapter provides a brief historical perspective then introduces the basic theory, terminology, and generic structural and functional features of ion channels. In addition, an overview of relevant ion channel methodologies is provided. The chapter aims to set the scene and to equip the non-specialist reader with sufficient background and understanding to comprehend and enjoy subsequent chapters which provide a more detailed analysis of channel families and individual channels.

Classification of 5-hydroxytryptamine (5-HT, serotonin) receptors in the guinea pig ileum into ‘D’ receptors located on smooth muscle cells and those located on intramural cholinergic neurones of the myenteric plexus (M type) has been superseded by the classification into ‘5-HT₁-like’, 5-HT₂, and 5-HT_3. Pharmacological analysis of the 5-HT₂ receptor suggested that it was identical to Gaddum's ‘D’ receptor. The 5-HT₃ receptor appears to be the acceptor component of a ligand-gated cation channel which bears comparison with the nicotinic acetylcholine-operated ion channel. Serotonergic activation causes a rapid depolarizing response associated with an increase in the membrane conductance to Na⁺ and K⁺ ions. The explosion of interest in this receptor subtype and the plethora of new and very selective 5-HT₃ antagonists owe much of their origin to pioneer studies undertaken in the late 1970s. 2-Methyl-5-HT is a potent agonist at 5-HT₃ receptors, but it also has high affinity for 5-HT_1D receptors and appreciable affinity for 5-HT_1A and 5-HT_lc sites. Phenylbiguanide, on the other hand, appears to be a much more selective 5-HT₃ agonist. However, phenylbiguanide does cause carrier-mediated release of dopamine from slices of rat caudate which bodes caution in interpretation of its effects in intact tissues.

In the previous chapters, we studied the spread of the membrane potential in passive or active neuronal structures and the interaction among two or more synaptic inputs. We have yet to give a full account of ionic channels, the elementary units underlying all of this dizzying variety of electrical signaling both within and between neurons. Ionic channels are individual proteins anchored within the bilipid membrane of neurons, glia, or other cells, and can be thought of as water-filled macromolecular pores that are permeable to particular ions. They can be exquisitely voltage sensitive, as the fast sodium channel responsible for the sodium spike in the squid giant axon, or they can be relatively independent of voltage but dependent on the binding of some neurotransmitter, as is the case for most synaptic receptors, such as the acetylcholine receptor at the vertebrate neuromuscular junction or the AMPA and GABA synaptic receptors mediating excitation and inhibition in the central nervous system. Ionic channels are ubiquitous and provide the substratum for all biophysical phenomena underlying information processing, including mediating synaptic transmission, determining the membrane voltage, supporting action potential initiation and propagation, and, ultimately, linking changes in the membrane potential to effective output, such as the secretion of a neurotransmitter or hormone or the contraction of a muscle fiber. Individual ionic channels are amazingly specific. A typical potassium channel can distinguish a K+ ion with a 1.33 Å radius from a Na+ ion of 0.95 Å radius, selecting the former over the latter by a factor of 10,000. This single protein can do this selection at a rate of up to 100 million ions each second (Doyle et al, 1998). At the time of Hodgkin and Huxley’s seminal study in the early 1950s, two broad classes of transport mechanisms were competing as plausible ways for carrying ionic fluxes across the membrane: carrier molecules and pores. At the time, no direct evidence for either one existed. It was not until the early 1970s that the fast ACh synaptic receptor and the Na channel were chemically isolated and purified and identified as proteins.

Adsorption experiments involving soil particles typically are performed in a sequence of three steps: (1) reactio of an adsorptive (ion or molecule) with a soil contacting an aqueous solution of known composition under controlled temperature and applied pressure for a prescribed period of time, (2) separationof the wet soil slurry from the supernatant aqueous solution, and (3) quantitationof the ion or molecule of interest, both in the aqueous solution and in the separated soil slurry along with its entrained soil solution. The reaction step can be performed in either a closed system (batch reactor) or an open system (flow-through reactor), and it can proceed over a time period that is either relatively short (to investigate adsorption kinetics) or very long (to investigate adsorption equilibration). The separation step is similarly open to choice, with centrifugation, filtration, or gravitational settling being conventional methods to achieve separation. The quantitation step, in principle, should be designed not only to determine the moles of adsorbate and unreacted adsorptive, but also to verify whether unwanted side reactions, such as precipitation of the adsorptive or dissolution of the adsorbent, have influenced the experiment. After reaction between an adsorptive i and a soil adsorbent, the moles of i adsorbed per kilogram of dry soil is calculated with the standard equation ni ≡ niT − Mwmi where niT is the total moles of species i per kilogram dry soil in a slurry (batch process) or a soil column (flow-through process), Mw is the gravimetric water content of the slurry or soil column (measured in kilograms water per kilogram dry soil), and mi is the molality (moles per kilogram water) of species i in the supernatant solution (batch process) or effluent solution (flow-through process). Equation 8.1 defines the surface exces, ni, of an ion or molecule adsorptive that has become an adsorbate. Formally, ni is the excess number of moles of i per kilogram soil relative to its molality in the supernatant solution. As mentioned in Section 7.2, this surface excess may be a positive, zero, or negative quantity.

The electron density in transition metal complexes is of unusual interest. The chemistry of transition metal compounds is of relevance for catalysis, for solid-state properties, and for a large number of key biological processes. The importance of transition-metal-based materials needs no further mention after the discovery of the high-Tc superconducting cuprates, the properties of which depend critically on the electronic structure in the CuO2 planes. The results of theoretical calculations of systems with a large number of electrons can be ambiguous because of the approximations involved and the frequent occurrence of low-lying excited states. The X-ray charge densities provide independent evidence from a technique with very different strengths and weaknesses, and thus can make significant contributions to our understanding of the properties of transition-metal-containing molecules and solids. In inorganic and organometallic solids, the average electron concentration tends to be high. This means that absorption and extinction effects can be severe, and that the use of hard radiation and very small crystals is frequently essential. Needless to say that the advent of synchrotron radiation has been most helpful in this respect. The weaker contribution of valence electrons compared with the scattering of first-row-atom-only solids implies that great care must be taken during data collection in order to obtain reliable information on the valence electron distribution. When the field exerted by the atomic environment is not spherically symmetric, as is the case in any crystal, the degeneracy of the d-electron orbitals is lifted. In the electrostatic crystal field theory, originally developed by Bethe (1929) and Van Vleck (1932), all interactions between the transition metal atom and its ligands are treated electrostatically, and covalent bonding is neglected. Since the ligands are almost always negatively charged, electrons in orbitals pointing towards the ligands are repelled more strongly, and the corresponding orbitals will be higher in energy. The discussion is the simplest for the one d-electron case, in which d-d electron repulsions are absent.

In most undergraduate chemistry classes, students are taught to consider reactions in which cations and anions dissolved in water are depicted as isolated ions. For example, the magnesium ion is depicted as Mg2+, or at best Mg2+(aq). For anions, these descriptions may be adequate (if not accurate). However, for cations, these abbreviations almost always fail to describe the critical chemical attributes of the dissolved species. A much more meaningful description of Mg2+ dissolved in water is [Mg(H2O)6]2+, because Mg2+ in water does not behave like a bare Mg2+ ion, nor do the waters coordinated to the Mg2+ behave anything like water molecules in the bulk fluid. In many respects, the [Mg(H2O)6]2+ ion acts like a dissolved molecular species. In this chapter, we discuss the simple solvation of anions and cations as a prelude to exploring more complex reactions of soluble oxide precursors called hydrolysis products. The two key classes of water–oxide reactions introduced here are acid–base and ligand exchange. First, consider how simple anions modify the structure and properties of water. As discussed in Chapter 3, water is a dynamic and highly fluxional “oxide” containing transient rings and clusters based on tetrahedral oxygen anions held together by linear hydrogen bonds. Simple halide ions can insert into this structure by occupying sites that would normally be occupied by other water molecules because they have radii (ranging from 0.13 to 0.22 nm in the series from F− to I−) that are comparable to that of the O2− ion (0.14 nm). Such substitution is clearly seen in the structures of ionic clathrate hydrates, where the anion can replace one and sometimes even two water molecules. Larger anions can also replace water molecules within clathrate hydrate cages. For example, carboxylate hydrate structures incorporate the carboxylate group within the water framework whereas the hydrophobic hydrocarbon “tails” occupy a cavity within the water framework, as in methane hydrate (see Chapter 3). Water molecules form hydrogen bonds to dissolved halide ions just as they can to other water molecules, as designated by OH−Y−.

In Chapters 4 and 5, we demonstrated that local structures and charge distributions have an enormous impact on the equilibrium constants, trajectories, and kinetics of reactions involving soluble oxide precursors. In this chapter, we highlight those features that make reactions on extended oxide surfaces either similar to or dramatically different from the reactions documented in hydrolysis diagrams for each metal cation (see Chapter 5). We first describe oxide surface structures and then discuss how these structures impact both acid–base and ligand-exchange phenomena. In addition to dense oxides, we also introduce some of the chemistry associated with layered materials. Lamellar materials are important from both a fundamental and technological perspective, because water and ions can readily penetrate such structures and provide conditions under which almost every oxygen anion is at an oxide–water interface (see Chapter 10 and Chapter 11). This chapter focuses on oxides containing octahedral cations. The distinctive chemistry of oxides based on tetrahedral cations, including the clay minerals and the zeolites, are the focus of Part Five. The structures of bulk oxides were introduced in Chapter 2. However, for many oxides, the surface structures that interact with aqueous solutions are substantially different from structures found in the bulk. Here, we introduce the basic principles of oxide surfaces that make them chemically active. As a starting point, consider ideal oxide surfaces containing +2 octahedral cations. Pristine oxide surfaces can be created by cleaving perfect crystals in an ultrahigh-vacuum environment. The creation of new surfaces requires an expenditure of energy corresponding to the cohesive energy of the solid, which in turn represents the energy required to break every bond along a given fracture plane. For MgO, the Mg−O bond energy is 380 kJ/mole. Each surface created contains 1.4.1019 oxygen atoms/m2, or 2.4.10−5 moles of bonds. Because two surfaces are created in the fracture event, the initial interfacial energy of each resulting MgO surface is (1/2)(380 kJ/mole)/(2.4_10−5 mole/m2 )=4560 mJ/m2.