Receptor activation mechanism

Hansen LF, Nielsen GD Sensory irritation and pulmonary irritation of -methyl ketones Receptor activation mechanisms and relationships with threshold limit values. Arch Toxicol 68 193-202, 1994... 

The receptors of steroid hormones were the first representatives of the family of nuclear receptors to be characterized. With the characterization of further receptors it became clear that the signaling pathway of the nuclear receptors differ significantly in detail. Based on the receptor activation mechanism the nuclear receptors can be divided into two basic groups ... 

This technology allows the sensitive analysis of small conformational changes and will ultimately allow an understanding of the receptor activation mechanism. These studies have shown two distinct switch mechanisms in the / -adrenergic receptor, both located in the third intracellular loop and the cytoplasmic end of transmembrane helix VI an ionic lock mechanism that involves an interaction of the cytoplasmic ends of helix VI and helix III (and is reported by a label in position 271 of the receptor), and a rotamer toggle switch mechanism that is reported by a label in position 265 (Yao et al, 2006). 

It is unknown whether or not TMVI movements play a role in the CCR5 receptor activation mechanism. Overall, a molecular understanding of activation mechanism for CCR5 and other chemokine receptors requires further biophysical studies of transmembrane helix positions and displacements. 

A number of hypotheses regarding the receptor activation mechanisms and its dynamics have been proposed [3,4]. 

Based on the receptor activation mechanism, the nuclear receptors may be divided into two basic groups. In the first group (those including most of the steroid hormone receptors), the receptors can be localized in the nucleus or in the cytoplasm. The receptors of the other group (discussed in Section 4.7) are always localized in the nucleus. Representative ligands of these receptors are the derivatives of retinoic acid, the T3 hormone and VitD3. 

The most probable mechanism for inverse agonism is the same one operable for positive agonism namely, selective receptor state affinity. However, unlike agonists that have a selectively higher affinity for the receptor active state (to induce G-protein activation and subsequent physiological response) inverse agonists have a selectively higher affinity for the inactive receptor state and thus uncouple already spontaneously coupled [RaG] species in the system. 

The first idea to consider is the effect of receptor density on sensitivity of a functional system to agonists. Clearly, if quanta of stimulus are delivered to the stimulus-response mechanism of a cell per activated receptor the amount of the total stimulus will be directly proportional to the number of receptors activated. Figure 5.8 shows Gi-protein-mediated responses of melanophores transiently transfected with cDNA for human neuropeptide Y-l receptors. As can be seen from this figure, increasing receptor expression (transfection with increasing concentrations of receptor cDNA) causes an increased potency and maximal response to the neuropeptide Y agonist PYY. 

The regulation of the total peripheral resistance also involves the complex interactions of several mechanisms. These include baroreflexes and sympathetic nervous system activity response to neurohumoral substances and endothelial factors myogenic adjustments at the cellular level, some mediated by ion channels and events at the cellular membrane and intercellular events mediated by receptors and mechanisms for signal transduction. As examples of some of these mechanisms, there are two major neural reflex arcs (Fig. 1). Baroreflexes are derived from high-pressure barorecep-tors in the aortic arch and carotid sinus and low-pressure cardiopulmonary baroreceptors in ventricles and atria. These receptors respond to stretch (high pressure) or... 

A condition in which a receptor is unresponsive despite the presence of agonist also referred to as a refractory state . Typically this state is the consequence of prolonged exposure to agonist, and occurs after receptor activation it is a built in mechanism to limit a receptor s effects. Mechanistically the desensitised state differs from the resting, closed state of a receptor because in the latter state, a receptor can respond to agonist. This difference predicts that these states are structurally distinct. The desensitised state may also be stabilised by very low concentrations of agonist, such that no measurable activation of the receptor precedes it. Desensitisation is an intrinsic property of many receptors but can also be influenced by other interactions or modifications, such as phosphorylation. 

Original Strnctnre and Activation Mechanism of mGIn Receptors... 

Figure 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

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