Activation of -receptors

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Competitive antagonists affinity of, 261-264 description of, 75 IC50 correction factors for, 223 Schild analysis, 261-264 Concentration-dependent antagonism, 99 Concentration-response curve, 13 Confidence intervals, 228-229 Conformations, 13-14 Constitutive activity of receptors description of, 49—51 receptor density and, 56 Schild analysis, 108-111 Context-dependent biological effect, 188 Correction factors, 211-213, 223 Correlational research, 231 CP320626, 128... 

Xue L, Stahura FL, Godden JW, Bajorath J. Mini-fingerprints detect similar activity of receptor ligands previously recognized only by three-dimensional pharmacophore-based methods. J Chem Inf Comp Sci 2001 41 394-401. 

To address whether the co-expression of CXCL12 and CXCR4 results in the activation of receptor signaling, Woemer et al. (2005)examined astrocytomas of various grades, Yang et al. (2007) examined medulloblastoma specimens, and Warrington et al. (2007) examined Neurofibromatosis Type-1 associated pilocytic... 

Lefkowitz, RJ, Cotecchia, S, Samama, P and Costa, T (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. TIPS 14 303-307. 

The organization of chemokine families based on the cysteine sequence has functional significance. Some human chemokines can compete for binding and activation of receptors with other intrafamily chemokines. This raised the possibility that significant structural differences in chemokine-receptor interactions... 

FIGURE 8.4 Branching of the signal-transduction pathways. Following activation of receptor PTK, several signal-transduction pathways can be activated, five of which are indicated here (see text for further details). 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Similarly, activation of neutrophils with PMA can also increase CR1 expression by a factor of 2-3, whereas CRl-dependent phagocytosis is enhanced 20-30-fold. This, again, may be due to activation of receptor function as well as to increasing receptor number on the cell surface. In addition... 

Insulin, growth factors Monomeric Tyrosine kinase activity of receptor Insulin Insulin-like growth factor (IGF) Platelet-derived growth factor (PDGF) Epidermal growth ftictor (EGF)... 

Schwartz, 1. C., Morisset, S., Rouleau, A., et al. (2003) Therapeutic impUcations of constitutive activity of receptors the example of the histamine H receptor. J. Neural. Transm. Suppl. 1-16. 

Despite a few differences, activation of -receptors generally leads to excitement, while )32-receptors generally are responsible for relaxation of tissue. Activation of P -receptors results in a stimulatory effect on the heart and kidneys, while activation of presy-naptic adrenergic receptors possibly suggests a feedback mechanism, which is the inhibition of neuronal norepinephrine release. At the same time, stimulation of postsynap-tic a2-receptors, as with aj-receptors, causes tissue excitement. 

The cellular consequences of neurotransmission can be both short term (acute) and long term (chronic). Acutely, stimulation of neurotransmitter receptors alters levels of intracellular signaling molecules, which may induce the neuron to fire or alter the responsiveness of the neuron to further stimulation. Over time, the persistent activation of receptors that occurs with... 

Activation of receptors can also be mediated by proteolytic cleavage of the extracellular domain of the receptor by proteases like thrombin. For these protease activated receptors, a proteolytically produced peptide functions as the activating ligand. 

---