Negative modulation

GABA is the most prominent inhibitory neurotransmitter in the mammalian nervous system and acts via GABA receptors. Activation of GABAb receptors by GABA released from local spinal interneurons (Fig. 1) negatively modulates nociceptive transmission in the spinal cord. Agonists at GABAb receptors... 

Figure 1.9 The NMD A receptor, showing the sites of interaction for glutamate (Glu), glycine (Gy), polyamine, Zn2+and Mg2+. Glutamate requires the presence of glycine to open the receptor channel. Polyamine positively modulates, and Zn2+and Mg2+negatively modulate, the opening of the channel. Ketamine and phencyclidine bind to the site labelled PCP.

Other heterotropic allosteric enzymes respond to an activator by an increase in Fmax with little change in if0i5 (Fig. 6-29c). A negative modulator (an inhibitor) may produce a more sigmoid substrate-saturation curve,... 

FIGURE 6-29 Substrate-activity curves for representative allosteric enzymes. Three examples of complex responses of allosteric enzymes to their modulators, (a) The sigmoid curve of a homotropic enzyme, in which the substrate also serves as a positive (stimulatory) modulator, or activator. Note the resemblance to the oxygen-saturation curve of hemoglobin (see Fig. 5-12). (b) The effects of a positive modulator (+) and a negative modulator (—) on an allosteric enzyme in which K0 5 is altered without a change in Zmax. The central curve shows the substrate-activity relationship without a modulator, (c) A less common type of modulation, in which Vmax is altered and /C0.sis nearly constant. 

This first enzyme, whose activity is modulated by an end-product, is an allosteric enzyme where, in addition to the active site, it has another space specific for binding the ligand which modulates the active site. Some negative modulators inhibit, as shown above with isoleucine on threonine hydratase, while others may stimulate or positively modulate the enzyme. Some enzymes have only one modulator and are called monovalent, while others have have several and are called polyvalent modulators. Moreover, some allosteric enzymes have both negative and positive modulators. Figure S.33 illustrates some patterns of allosteric modulation. The advantage of these control systems is that cellular materials are economically used. 

Fig. 5.35. Effect of positive and negative modulators of reaction rate. Substrate concentration - rate curves for...

Other actions of some anticonvulsants include inhibition of the enzyme carbonic anhydrase, negative modulation of calcium channel activity, and actions on second messenger systems, including inhibition of phosphokinase C. Beyond the second messenger, there is the possibility that second messenger systems may be affected, analogously to what is hypothesized for lithium. 

Other authors showed that (R)a-methylhistamine, together with the inotropic and chronotropic adrenergic response from transmurally-stimulated atrial preparations, also inhibits the release of noradrenaline, thus providing direct evidence that histamine H3-receptors negatively modulate the cardiac sympathetic activity at a presynaptic site of action (Endou et al., 1994). In addition, it was demonstrated that (R)a-methylhistamine, at concentrations greater than 1 pM, produces further antiadrenergic activity by acting at inhibitory presynaptic a.2-adrenoceptors. This result is supported by the fact that yohimbine reverses this effect. 

Figure 10. Scheme illustrating the main locations and functional role of H3 receptors in the vessels. H3 receptors coupled with inhibitory G proteins (Gj) occur as prejunctional receptors in the adrenergic varicosities, where they negatively modulate noradrenaline (NA) release. Moreover, their activation in endothelial cells can induce muscle relaxation, by the release of inhibitory factors, such as nitric oxide (NO) and prostacyclin (PGI2). In some districts, excitatory H3 receptors were found in muscle cells and they mediate muscle contraction. MC = mast cell NOS = NO synthase COX = cyclooxygenase. 

Patel, S., Roelke, C. T., Rademacher, D.J., Cullinan, W. E., and Hillard, C.J. (2004). Endocanna-binoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145, 5431-5438. 

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