Cell membrane, receptor/ligand binding

Figure 5. General two-step fluidity hypothesis for the mechanism of modulation of effectors in cell membranes by ligands. The central feature is that the receptors and the effectors are discrete and separate structures that acquire specificity and affinity for complex formation only after the receptor has been occupied by the ligand. These structures can combine after binding of the ligand because of the fluidity of cell membranes. The ligand binding sites of the receptor are on the external face, exposed to the aqueous medium, and the active site of the effector (enzyme) is facing inward toward the cytoplasm of the cell. After Cuatrecasas (124).

Extracellular ligands (hormones, neurotrophins, carrier protein, adhesion molecules, small molecules, etc.) will bind to specific transmembrane receptors. This binding of specific ligand induces the concentration of the receptor in coated pits and internalization via clathrin-coated vesicles. One of the best studied and characterized examples of RME is the internalization of cholesterol by mammalian cells [69]. In the nervous system, there are a plethora of different membrane receptors that bind extracellular molecules, including neurotrophins, hormones and other cell modulators, being the best studied examples. This type of clathrin-mediated endocytosis is an amazingly efficient process, capable of concentrating... 

Calcineurin is part of a signaling pathway that is activated by a rise in intracellular calcium upon ligand binding to a cell membrane receptor. The rise in Ca activates calcineurin s phosphatase activity, which dephosphorylates cytoplasmic NF-AT transcription factor family members. Dephosphorylated NF-AT-members enter the nucleus and bind to DNA in cooperation with other transcription factors, e.g. AP-1. By this way many target genes in diverse tissues can be activated. 

The extracellular domain of cell membrane receptors can be produced recombi-nantly and used as a therapeutic product. The soluble receptor can be used to bind and neutralize the receptor s endogenous ligands (e.g., etanercept), or it can be used for stimulation of a co-receptor (e.g., abatacept). Soluble receptors are typically produced as IgG Fc fusion proteins to extend the half-life of the receptor in circulation. 

Quirk PL, et al. Three putative N-glycosylation sites within the murine 5-HT3A receptor sequence affect plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells. J Neurosci Res 2004 77(4) 498-506. 

Therefore, we can expect that coupling reactions between two membrane-associated species will commonly be diffusion-limited. This result is in contrast to that for receptor/ligand binding in solution, which will not typically be diffusion-limited, and to that for ligand binding to cell surface... 

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