Principles of Receptor Research
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Receptors display a wide range of state-dependent endocytosis rates, but the functional significance of these patterns was not understood.
Using mathematical analysis, they showed that receptor system efficiency and robustness are encoded by two fundamental parameters: the avidity , which quantifies the ability of a receptor system to capture ligand, and the consumption , which quantifies the ability to internalize bound ligand see figure. By examining a number of receptor systems see figure , the researchers demonstrated that receptor system response can be characterized as being either avidity-controlled, which depends primarily on ligand capture efficiency; consumption-controlled, where the ability to internalize surface-bound ligand is the primary control parameter; and dual-sensitive, in which both the avidity and consumption parameters are important.
A Tipping Point in Clinical Development
The location of various receptor systems in control parameter space dictates their specific function and regulation. Most significantly, the researchers believe that the evolution of a given receptor system can be understood in terms of its optimal location in avidity-consumption parameter space.
For example, induced endocytosis can be shown to be an optimal solution for transmitting high-fidelity information by signaling receptors. What's next: In a related article not yet published, the same team of researchers shows that biological signaling networks can be understood in the context of human-engineered electrical and mechanical systems.
The Nobel Prize in Physiology or Medicine 1988
By analyzing a widely used receptor signaling module, they show that the module behaves like an electronic low-pass filter with a definite frequency bandwidth or as a damped mechanical oscillator. Even though the dynamical parameters may be quite specific to a particular receptor system, the underlying structure of the module is essentially the same for different signaling receptors. Steroid hormone ligands for this subgroup of receptors travel from their respective endocrine gland through the bloodstream bound to steroid binding globulin.
Some type 1 nuclear receptors are activated, in part, upon binding their respective ligand in the cytoplasmic compartment.
The Principles of Ligand Specificity on beta-2-adrenergic receptor
The ligand-receptor complex enters the nucleus where it homodimerizes, dissociates from HSP90, and binds a hormone response element within the promoter of a target gene. The receptor transactivation domain is responsible for interaction at the promoter with acetyltransferases, co-activators, and the general transcription machinery TBP, TFIIB, RNA polymerase II , thereby resulting in transcriptional activation.
Members of this family heterodimerize with the retinoid X receptor RXR. Prior to ligand binding, receptor heterodimers are located in the nucleus as part of complexes with histone deacetylases HDACs and other co-repressors that keep target DNA in a tightly wound conformation, preventing exposure to transactivation factors.
Ligands & receptors (article) | Khan Academy
Ligand binding results in HDAC dissociation, chromatin derepression, and transcriptional activation. In addition to ligand binding, nuclear receptor activity can be modulated through the action of numerous growth factor and cytokine signaling cascades that result in receptor phosphorylation or other post-translational modifications, typically within the N-terminal transactivation domain. For example, the estrogen receptor is phosphorylated on multiple serine residues that affect receptor activity.
Phosphorylation of Ser may confer resistance to tamoxifen in breast cancer patients.
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