Search Results

Ionotropic glutamate receptors, including NMDA receptors, mediate most of the excitatory synaptic transmission in the mammalian central nervous system. When NMDA receptors are activated by membrane depolarization, a relatively slow-rising, long-lasting current develops, which allows the summation of responses to stimuli for a relatively long periods (tens of milliseconds). In addition to their role in synaptic transmission, NMDA receptors affect functions that are critical for the survival and differentiation of cells and for synaptic plasticity, in part through Ca²⁺-dependent signal transduction. In addition, receptor activation elicits long-term changes in cellular functions, mediated through interactions (either directly or via scaffolding proteins) with signaling systems, including protein kinase cascades that lead to modulation of gene transcription. This chapter discusses the unique role of NMDA receptors in excitatory transmission, their molecular structure, posttranslational modifications (phosphorylation and dephosphorylation), molecular interactions relevant for signal transduction, desensitization, anatomical distribution, pharmacology, modulation of expression in transgenic mice, and therapeutic applications.

Learning is behavioural modification resulting from experience. Since all behaviour reflects actions of the nervous system, behavioural modification must result from changes in the behaviour of the nervous system. Hence, lasting plasticity in neuronal function is a prerequisite for learning. Biophysical substrates for neuronal plasticity have been examined in the vertebrate. At the synaptic level, plasticity is expressed by changes in the amount of transmitter released or in the sensitivity of postsynaptic receptors for the transmitter. Although each synaptic function that is modulated during plasticity must be described individually, we can begin to discern some features common to several systems at the molecular level. For example, persistent plastic changes appear to require the activation of intracellular second messengers or the phosphorylation of certain proteins.

Living systems create order, and appear to break the Second Law. This chapter explains, and resolves, this apparent paradox, drawing on the concept of coupled reactions (as introduced in Chapters 13 and 16), as mediated by ‘energy currencies’ such as ATP and NADH. The chapter then examines the key energy-capturing systems in biological systems – glycolysis and the citric acid cycle, and also photosynthesis. Topics covered include how energy is captured in the conversion of glucose to pyruvate, the mitochondrial membrane, respiration, electron transport, ATP synthase, chloroplasts and thylakoids, photosystems I and II, and the light-independent reactions of photosynthesis.

Higher functions of the central nervous system are based on communication between functional units consisting of many neurons. Communication within and between functional units of neurons is largely based on the chemical transmission of signals with time courses ranging from milliseconds to seconds and minutes. Most chemical transmission requires a cascade of enzymatic steps that are relatively slow, but provide for essential modulation of fast transmission and of effects that are independent of ion channels. This typically involves receptors that are coupled to membrane-bound, GTP-binding proteins (G proteins). This chapter discusses G-protein-coupled signal transduction, protein phosphorylation, multifunctional CaM kinase, and functional studies.

Among the most significant changes induced in monoaminergic neurones by chronic antidepressant treatment are: reduction in tyrosine hydroxylase activity, decrease in the ability of NA to stimulate the activity of adenylate cyclase, and reduction in the concentration of noradrenergic and serotonergic receptors. Many synaptic and trans-synaptic mechanisms may participate in the desensitization of neurotransmitter receptors after chronic treatment with antidepressants. The most commonly described effector mechanism beyond the second messengers depends on protein phosphorylation mediated by activation of specific protein serine-threonine kinases. Components of the protein phosphorylation system are associated with the cytoskeleton. This chapter investigates whether the cAMP-dependent phosphorylation system associated with microtubules, which are constituents of neuronal cytoskeleton, could be an intracellular target for antidepressants acting on NA and 5-HT neurones.

Beside their action at the genomic level, estrogens such as 17β-estradiol (E2) also activate rapid and transient cellular, physiological, and behavioral changes. Aromatase is the key limiting enzyme in the production of estrogens and the rapid modulation of this enzymatic activity could produce rapid changes in local E2 concentrations. The mechanisms that might mediate such rapid enzymatic changes are thus currently under intense scrutiny. Recent studies in our laboratory indicate that brain aromatase activity is rapidly inhibited by an increase in intracellular calcium concentration that results from potassium-induced depolarization or from the activation of glutamatergic receptors. Altogether, the phosphorylation/dephosphorylation processes affecting aromatase activity provide a new general mechanism by which the concentration of estrogens can be rapidly altered in the brain and other tissues.

Three turns of the Calvin cycle (Figure 11.1), allow the conversion of three (3) equivalents of carbon dioxide (CO2) (i.e., 3 C1 units) along with three (3) equivalents of the five-carbon carbohydrate derivative, ribulose-1,5-bisphosphate (i.e., 3 C5 units) to yield three (3) not yet isolated six-carbon adducts, 2-carboxy-3-ketoribitol-1,5-bisphosphate (3 C1 + 3 C5 = 3 C6) to form. The three (3) C6 species then undergo fragmentation to yield six (6) equivalents of the three (3) carbon dihydroxy monocarboxylate, 3-phosphoglycerate (i.e., 3 C6 = 6 C3). A cartoon representation of this process is shown in Scheme 11.1 for one of the three CO2 units. Of the six (6) three-carbon unit equivalents, five (5) are used to regenerate three (3) equiv¬alents of ribulose-1,5-bisphosphate (i.e., 5 C3 = 3 C5), while the sixth three- carbon fragment is now available to combine with another to make a six (6) carbon sugar (2 C3 = 1 C6) such as glucose (C6H12O6) (Figure 11.2). Additionally, as shown in Figure 11.3, 3-phosphoglycerate can be used to make other small compound building blocks such as glyceric acid, lactic acid, pyruvic acid and even acetic acid (after decarboxylation). Ribulose- 1,5-bisphosphate (often abbreviated as RuBP), using the enzyme ribulose- 1,5- bisphosphate carboxylase (EC 4.1.1.39, carboxydismutase, rubisco), catalyzes the Mg2+- dependent conversion of the 1,5- bisphosphate ester of the carbohydrate ribulose with carbon dioxide (CO2) to produce two (2) equivalents of 3- phosphoglycerate (PGA). As shown in the Schemes 11.1 and 11.2. A hypothetical the six carbon intermediate, 2- carboxy- 3- ketoribitol- 1,5- bisphosphate, is often written. It is important to keep in mind that we want the 3- phosphoglycerate for purposes of construction of other important compounds. But, as noted above, three turns of the cycle are necessary to produce six (6) equivalents of 3- phosphoglycerate, and five (5) of them are reused in making the three (3) ribulose- 1,5- bisphosphates necessary to turn the cycle three (3) times.

This chapter presents a treatment of “retroactivity to interconnections.” It outlines some of the design challenges found in biomolecular systems from a systems engineering perspective, in particular, the problem of modularity. It proposes a framework for quantifying retroactivity at interconnections between transcriptional circuits and provides a mechanism to counteract retroactivity. This chapter reveals that simple cycles, involving phosphorylation and dephosphorylation, enjoy intrinsic insulation properties, and thus have the potential to serve as synthetic biomolecular insulation devices. It suggests that the design of the biomolecular circuit presents many challenges to systems and control engineers.

This chapter describes and elaborates on the energy coupling processes of living systems. First, equilibrium and nonequilibrium systems are discussed, introducing living systems as open, nonequilibrium, and dissipative structures continuously interacting with their surroundings. The roles of thermodynamics and Gibbs free energy as they apply to energy coupling phenomena are then summarized, followed by a discussion of protein structures as playing a crucial role in information processes and energy couplings. The “well-informed” character of living systems and the control of free energy, or exergy, by information are also briefly discussed. Finally, using the linear nonequilibrium thermodynamic approach, energy couplings in ATP production through oxidative phosphorylation and active transport of ions by chemical pumps are discussed as a part of bioenergetics.

Mechanisms of dopamine-mediated incentive learning explains how sensory events, resulting from an animal’s movement and the environment, activate cortical glutamatergic projections to dendritic spines of striatal medium spiny neurons to initiate a wave of phosphorylation. If no rewarding stimulus is encountered, a subsequent wave of phosphatase activity undoes the phosphorylation. If a rewarding stimulus is encountered, dopamine initiates a cascade of events in D1 receptor-expressing medium spiny neurons that may prevent the phosphatase effects and work synergistically with signaling events produced by glutamate. As a result, corticostriatal synapses have a greater impact on response systems; this may be part of the mechanism of incentive learning. Dopamine acting on dendritic spines of D2 receptor-expressing medium spiny neurons may prevent synaptic strengthening by inhibiting adenosine signaling; these synapses may be weakened through mechanisms involving endocannabinoids. When dopamine concentrations drop, e.g. during negative prediction errors, the opposite may occur, producing inverse incentive learning.

Chromatin is refractory to the process of transcription and must be modified to allow access to the DNA. The usual initial step of this modification is the binding of “pioneering” transcription factors to their cognate sequences. These factors then recruit chromatin remodeling and modifying complexes. Nucleosomes can be displaced, or their association with DNA can be altered by multiprotein complexes that hydrolyze ATP to generate the energy necessary for their functions. Other complexes replace certain canonical histones with specific histone variants. Histones can undergo acetylation, methylation, phosphorylation, ubiquitination, sumoylation, glycosylation, ADP ribosylation or hydroxyisobutyrylation of particular amino acids along their molecules. DNA nucleotides can be modified by methylation or hydroxymethylation, without altering the coding sequences. All of these chromatin changes are associated with gene function, with sets of modifications usually present on active or repressed genes. Not surprisingly, mutations that affect the timely occurrence or removal of these modifications result in particular diseases.

Probably no process epitomizes life more than respiration. By respiration we mean the cascade of energy-producing biochemical reactions called oxidative phosphorylation, powered by a gradient of oxidation. Structure and function are intimately connected, forming an entity called a faculty. In this book, we focus on the functional and evolutionary morphology of the respiratory faculty, many of the components of which are older than the first animals, indeed older than life itself. The initial steps until the first animals arose are summarized here in a hypothetical scenario and provided together with an introduction to several other conceptual approaches that we have adhered to throughout this book.