Receptor-mediated intracellular signalling

Many transmembrane proteins that mediate intracellular signaling form complexes with both intra- and extracellular proteins. For example, neural cell adhesion molecules (NCAMs) are cell-surface glycoproteins (Ch. 7). The extracellular domains of NCAMs can activate fibroblast growth factor receptors when clustered by reaction with NCAM antibodies [4] or by homotypic binding to domains of adjacent cells (see Fig. 7-2). Activation was found to sequester a complex of NCAM, (31 spectrin and PKC(32 into rafts, as defined by the operational criteria discussed on p. 28. 

Inhibition of neurite growth is mediated through surface receptors and intracellular signaling molecules. 

Another class of receptors mediate intracellular responses through Ca2+ mobilisation. A specific class of phospholipids, the phosophoinositides play an important role in signal transduction from receptors at the plasma membrane. The cellular responses that use phosphoinositide hydrolysis and Ca2+ mobilisation are diverse, they include general metabolism, secretion, contraction, phototransduction and proliferation. An imbalance of the second messenger system in the proliferation cascade may be responsible for normal cells becoming cancerous. 

As observed with the other D2-like receptors, the D4 receptors mediate additional signaling events that are independent of the changes in cAMP levels. Some of these intracellular signals can be transduced by the Gpy complex. This is probably the case in HEK 293 transfected with a Gpy-sensitive adenylyl cyclase (ACII), in which activation of D4 receptor paradoxically produced a stimulation of cAMP production (Watts and Neve,... 

Figure 8. Schematic of membrane receptors lacking intrinsic enzymatic activity. Intracellular signaling is initiated by coupling of the receptor to an intracellular kinase (e.g JAK kinase). These receptors mediate cytokine signaling (prosurvival protective and maladaptive pathways leading to apoptosis). JAK/STAT signalling is involved in the cellular response to ischemia. Activation of STAT3 reduces ischemia induced apoptosis, whereas activation of STAT1 has the opposite effect.

Some transmembrane receptors have cytoplasmic protein phosphatase activity. Soluble protein phosphatases, such as calcineurin, PP1, PP2A, PP2C, and protein tyrosine phosphatases, also mediate intracellular signals. 

Shoham S, Huang C, Chen JM et al. Toll-like receptor 4 mediates intracellular signaling without TNF-a release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol 2001 166 4620-4626. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

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