Fast receptors

Some of the most revealing studies of partial agonism (including Stephenson s seminal work) have been done with tissues in which G-proteins (see Chapters 2 and 7) provide the link between receptor activation and initiation of the response. In contrast to the situation with fast receptors with intrinsic ion channels (see above), it is not yet possible to observe the activity of individual G-protein-coupled receptors (with the potential exception of some that are linked to potassium channels) however, enough is known to show that the mechanisms are complex. The interpretation of differences in efficacy for agonists acting at such receptors is correspondingly less certain. 

The macrobicyclic ligand derived from 4,13-diaaza-18-crown-6 and Schiff-base spacer (e.g., 1,2-phenylenediamine or 1,2-ethylenediamine) forms stable lead(n) complexes of general formula [LPb(X)2 (solv),] in the presence of different counterions <2005IC5428>. The double protonation of the resulting compounds causes the demetalation of the complex without receptor destruction. Since this demetalation process is reversible and very fast, receptor L has been suggested as potential compound for lead(ll) extraction. 

There are two types of receptor, termed fast and slow sites [21]. The fast responses (detectable in <5 min) appear to be brought about by membrane-mediated phenomena, while the slow responses, which involve protein synthesis, are not detectable within the first half hour. The receptor types have different molecular requirements, and the fast reaction is not a pre-requisite for the slow. Growth assays employed to assess activity include Avena coleoptile, lettuce hypocotyl, rice seedling, and bean axis. Other types include lettuce seed and wheat embryo germination, transpiration assays, leaf disk senescence, and more recently, a-amylase production. Stomatal closing using epidermal strips is an assay for the fast receptor. 

As an example for an efficient yet quite accurate approximation, in the first part of our contribution we describe a combination of a structure adapted multipole method with a multiple time step scheme (FAMUSAMM — fast multistep structure adapted multipole method) and evaluate its performance. In the second part we present, as a recent application of this method, an MD study of a ligand-receptor unbinding process enforced by single molecule atomic force microscopy. Through comparison of computed unbinding forces with experimental data we evaluate the quality of the simulations. The third part sketches, as a perspective, one way to drastically extend accessible time scales if one restricts oneself to the study of conformational transitions, which arc ubiquitous in proteins and are the elementary steps of many functional conformational motions. 

For large systems comprising 36,000 atoms FAMUSAMM performs four times faster than SAMM and as fast as a cut-off scheme with a 10 A cut-off distance while completely avoiding truncation artifacts. Here, the speed-up with respect to SAMM is essentially achieved by the multiple-time-step extrapolation of local Taylor expansions in the outer distance classes. For this system FAMUSAMM executes by a factor of 60 faster than explicit evaluation of the Coulomb sum. The subsequent Section describes, as a sample application of FAMUSAMM, the study of a ligand-receptor unbinding process. 

Eldridge M D, C W Murray, T R Auton, G V Paoliniand R P Mee 1997. Empirical Scoring Functions 1 The Development of a Fast Empirical Scoring Fimction to Estimate the Binding Affinity of Ligand in Receptor Complexes. Journal of Computer-Aided Molecular Design 11 425-445. 

From the kinetic point of view the facts are different and the order is reverse, ie, the rigid highly preorganized spherands are slow, as contrasted with the flexible barely preorganized podands that are fast both in formation and decomposition of the receptor—substrate (host—guest) complex (20,21). 

The low detection limit, high sensitivity, and fast response times of chemoreceptor-based biosensors result primarily from the extremely high binding constants of the receptor R for the target substrate S. The receptor—substrate binding may be described... 

Hemiequilibria, a pseudoequilibrium that can occur when a fast-acting agonist equilibrates with a receptor system where a slow acting antagonist is present. The agonist will occupy the nonantagonist bound receptors quickly and... 

Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics A new hypothesis. Am J Psychiatry 158 360-369... 

These include atropine, scopolamine (hyoscine), trihexyphenidyl (benzhexol) and benzatropine. They block central muscarinic receptors involved in various afferent pathways of the vomiting reflex (Fig. 1). They have been used to control motion sickness, emesis in Meniere s disease and postoperative vomiting. Currently, hyoscine is largely restricted to the treatment of motion sickness where it has a fast onset of action but a short duration (4-6 h). Administration of hyoscine by transdermal patch produces a prolonged, low-level release of the drug with minimal side effects. To control postoperative vomiting, it should be applied >8 h before emesis is anticipated. 

Whereas the role of AMPA and NMDA receptors in fast synaptic transmission is well characterized, only few examples demonstrating synaptic responses due to kainate receptor activation are known so far. 

In sympathetically innervated tissues, such as vas deferens or blood vessels, ATP produces fast responses mediated by P2X receptors followed by a slower component mediated by G protein-coupled a-adrenoceptors (Fig. 2) NPY usually acts as a pre-or postjunctional modulator of the release and/or action of NA and ATP. Similarly, for parasympathetic nerves supplying the urinary bladder, ATP provokes a fast, short-lasting twitch response via P2X receptors, whereas the slower component is mediated by G... 

Purinergic System. Figure 2 Schematic of sympathetic cotransmission. ATP and NA released from small granular vesicles (SGV) act on P2X and a-i receptors on smooth muscle, respectively. ATP acting on inotropic P2X receptors evokes excitatory junction potentials (EJPs), increase in intracellular calcium ([Ca2+]j) and fast contraction while occupation of metabotropic ar-adrenoceptors leads to production of inositol triphosphate (IP3), increase in [Ca2+]j and slow contraction. Neuropeptide Y (NPY) stored in large granular vesicles (LGV) acts after release both as a prejunctional inhibitory modulator of release of ATP and NA and as a postjunctional modulatory potentiator of the actions of ATP and NA. Soluble nucleotidases are released from nerve varicosities, and are also present as ectonucleotidases. (Reproduced from Burnstock G (2007) Neurotransmission, neuromodulation cotransmission. In Squire LR (ed) New encyclopaedia of neuroscience. Elsevier, The Netherlands (In Press), with permission from Elsevier). 

Specialization Each receptor contributes to morphologically (e.g., phasic vs. tonic) or temporally (early vs. late) distinct components of the overall response. This is the case of prolonged EFS-induced nonadrenergic, noncholinergic contraction the guinea pig colon or rat urinary bladder, where the fast and late components of the contraction are mediated by NKxror NK2r, respectively... 

It should be noted that fast inactivation of receptor signaling not only involves the desensitization of the receptor but also the components of the downstream signaling cascade. The deactivation of active Ga subunits is controlled by the intramolecular hydrolysis of bound GTP, allowing it to reform the inactive heterotrimer. Termination of G protein-mediated signaling in vivo is 10- to 100-fold faster than the in vitro rate of GTP hydrolysis by Ga subunits, suggesting... 

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