Biochemical cascade

The time-resolved aspect of domino processes would, however, be in agreement with cascade reactions as a third expression used for the discussed transformations. Unfortunately, the term cascade is employed in so many dilferent connections - for example, photochemical cascades, biochemical cascades or electronic cascades - on each occasion aiming at a completely dilferent aspect, that it is not appropriate moreover, it also makes the database search much more difficult Moreover, if water molecules are examined as they cascade, they are simply moving and do not change. Several additional excellent reviews on domino reactions and related topics have been published [7], to which the reader is referred. 

Cellular signals converge at the level of protein phosphorylation pathways. Individual intracellular messenger pathways, such as cAMP, Ca2+ and MAPK pathways, are often drawn as distinct biochemical cascades that operate in parallel in the control of cell function. While this is useful for didactic purposes, it is now well established that these various pathways function as complex webs, with virtually every conceivable type of interaction seen among them. 

Thus, a brief puff of chemical neurotransmission from a presynaptic neuron can trigger a profound postsynaptic reaction, which takes hours to days to develop and can last days to weeks or even longer. Every conceivable component of this entire process of chemical neurotransmission is a candidate for modification by drugs. Most psychotropic drugs act on the processes that control chemical neurotransmission at the level of the neurotransmitters themselves or of their enzymes and especially their receptors. Future psychotropic drugs will undoubtedly act directly on the biochemical cascades, particularly on those elements that control the expression of pre- and postsynaptic genes. Also, mental and neurological illnesses are known or suspected to affect these same aspects of chemical neurotransmission. 

The elevation of presynaptic Ca2+ causes synaptic vesicles to fuse with the plasma membrane and release neurotransmitter into the synaptic cleft. Neurotransmitters then diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane. This can result in the opening or closing of ion channels, thus changing the probability that the postsynaptic neuron will fire an action potential, or the triggering of biochemical cascades within the postsynaptic neuron (collectively termed signal transduction). In this manner, neuronal communication occurs as information is transmitted from the presynaptic membrane to the postsynaptic membrane, and thus from one neuron to another. 

In addition to cell-derived mediators, several acellular biochemical cascade systems act in parallel to initiate and propagate the inflammatory response. These include ... 

An action potential results in opening of VDCCs at the axon terminal. Entrance of Ca triggers a biochemical cascade to cause neurotransmitter-containing vesicles to fuse with the cell membrane and release acetylcholine into the synaptic cleft. 

Drug dose-effect relationships in biochemical cascades... 

The two statements are in fact related. In our example, a perfect similarity of theoretical and experimental plots could only be expected if there were a linear relationship between receptor saturation with norepinephrine and muscle contraction. Considering that muscle contraction is triggered quite a bit downstream of receptor activation, there are numerous possible factors that will distort this linearity, and in reality no linear relationship will ever be observed if drug target and drug effect are separated by intervening biochemical cascades. It thus turns out that the shape of a dose-effect relationship will depend very much on the functional proximity of the drug receptor molecule and the observed parameter. 

A hormone receptor typically triggers a biochemical cascade with multiple steps that need to occur before a functional effect is accomplished. This indirect coupling has surprising consequences for the relationship between the saturation of the receptor and that of the functional effect. We will consider the effect of cascading mediators in a very simple model , containing the following assumptions (Figure 3.7a) ... 

Figu re 3.7. Theoretical model to illustrate the effect of biochemical cascades on dose-effect relationships. a A simple model cascade, containing an agonist (L), a receptor (R), a second messenger (M2), and an effector (E). b Equations derived from the assumptions in a. ECjq Ligand concentration required for the half-maximal effect. The effect will saturate at concentrations lower than those required for receptor saturation. The gap between K and ECjq depends on the number of receptors and other properties of the system, c Illustration of the equations stated inb. 

Many members of this class of receptors have an enzymatic activity known as a protein tyrosine kinase within their cytoplasmic segment. This kinase phosphorylates tyrosine residues in the receptors themselves (autophosphory lation), and in other proteins to initiate biochemical cascades. Phosphorylatipn of tyrosine can be reversed by protein tyrosine phosphatases, which are also present in all cells (Shenolikar and Naim, 1990). Tyrosine phosphatases form a diverse family of proteins, some of which are cytosolic while others are transmembrane molecules analogous to receptors. Some members of the transmembrane class may be involved in the mechanism of bacterial and viral infections (Tonks, 1991). Thus, kinases and phosphatases together act as on-off switches in the a ctivation of receptors and other proteins. 

Studies at the U.S. Army Medical Research Institute of Chemical Defense are thus far consistent with the proposal that, with the exception of activation of hexose monophosphate shunt (Martens, 1994), this biochemical cascade may contribute to blister formation. In addition, however, the process would appear to require an active inflammatory response and altered fluid dynamics in the affected tissue to generate the very large blisters seen after sulfur mustard exposure. 

Following G-protein activation comes initiation of effector mechanisms. For example, this can include activation of the enzyme adenylyl cyclase to produce the second messenger cyclic AMP. This and other second messengers go on to activate enzymatic biochemical cascades within the cell. A second layer of response observation is the measurement of the quantity of these second messengers. Yet another layer of response is the observation of the effects of the second messengers. Thus, activation of enzymes such as MAP kinase can be used to monitor dmg activity. 

Introduction and Rationale. DHFR is an ideal system to study for a number of reasons. The catalytic properties of DHFR are such that under normal physiologic conditions and with the NADPH cofactor bound, 7,8-dihydrofolate (DHF) is reduced to 5,6,7,8-tetrahydrofolate (THF) (7). Thus DHFR plays an important role in cell metabolism by maintaining a supply of THF. THF is used by the cell as both a cofactor and in substrate quantities in the synthesis of deoxythymidine. By inhibiting the production of THF, deoxythymidine synthesis is curtailed, nucleic add replication comes to a halt, and cell proliferation ceases. It is this biochemical cascade which supplies the pharmacological and chemotherapeutic applications of inhibitors to DHFR. 

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