Intracellular domain

Figure 13.1 The basic organization of a membrane receptor molecule consists of an extracellular domain, a transmembrane region, and an intracellular domain.

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

The RTK activity phosphorylates tyrosine residues within the intracellular domain of the receptor. These phosphorylated residues function as docking sites for proteins that will convey the signal to downstream signal transduction components. PKI can be developed that bind these phosphorylated docking sites in order to abrogate inappropriate downstream signalling. 

Figure 28 The biophysical model for passive diffusion and concurrent intracellular metabolism of a drug for a simple A-to-B reaction process. Concentration-distance profiles are depicted in the aqueous boundary layer and intracellular domain for the drug and metabolite. The bottom diagram depicts the direction of the fluxes of drug and metabolite viewed from the donor and receiver sides of the cell monolayer. Details of basic assumptions are found in the text.

Yet another family of junction adhesion molecules (JAMs) was recently located at the tight junctions of both endothelial and epithelial cells. The intracellular domain of JAM-1 also interacts with structural and signaling proteins, such as ZO-1 and cingulin. Lastly, the molecular organization of the endothelial cell junctions includes two other cell-cell contact Ca2+-dependent cadherin-catenin systems. These make up the adherens junction common to all endothelial cell junctions. 

Chen et al. [62] have proposed that protein kinase C is involved in the fi receptor desensitization since activators of this enzyme potentate fi receptor uncoupling from the K+ channel. The fi receptor has consensus protein kinase C phosphorylation sites in its intracellular domains [8]. Arden et al. [88] have reported that morphine can induce the phosphorylation of the cloned fi receptor and Zhang et al. [64] have reported that activators of protein kinase C can induce the phosphorylation of the ft receptor. 

If ft receptors couple to K+ channels and adenylyl cyclase via different G proteins, it is possible that chronic morphine treatment uncouples the receptor from those G proteins linked to the K+ channel and not those coupling fi receptors to adenylyl cyclase. Such a hypothesis would require that G proteins couple to different intracellular domains of the fi receptor so that interaction of G proteins with some domains could be blocked by post-translational events, such as phosphorylation, whereas binding of G proteins to other fi receptor domains would not be affected. 

Mutagenesis studies have established that the C-terminal region of the // and S receptors is not essential for the receptors to couple to adenylyl cyclase [131, 132]. The remaining intracellular domains of the opiate receptors have almost identical amino acid sequences. As a consequence, it is likely that the intracellular loops are the main regions of the opiate receptor involved in G protein coupling and effector system regulation. 

Major differences in the amino acid sequences of the intracellular domains of the opiate receptors reside in the C-terminal tail [8]. While this domain is not essential for coupling to G proteins it may be important for the desensitization and internalization of the opiate receptors. 

Cytokine receptors can be divided into two groups those whose intracellular domains exhibit intrinsic protein tyrosine kinase (PTK) activity and those whose intracellular domains are devoid of such activity. Many of the latter group of receptors, however, activate intracellular soluble PTKs upon ligand binding. 

The IL-ls induce their characteristic biological activities by binding to specific cell surface receptors present on sensitive cells. Two distinct receptors, type I and II, have been identified. Both IL-la and IL-ip can bind both receptors. The type I receptor is an 80 kDa transmembrane glycoprotein. It is a member of the IgG superfamily. This receptor is expressed predominantly on fibroblasts, keratinocytes, hepatocytes and endothelial cells. The type II receptor is a 60 kDa transmembrane glycoprotein, expressed mainly on B-lymphocytes, bone marrow cells and polymorphonuclear leukocytes. It displays a very short (29 amino acid) intracellular domain,... 

Both receptor types are members of the NGF receptor superfamily and exhibit the characteristic four (cysteine-rich) repeat units in their extracellular domain. The extracellular domains of TNF-R55 and TNF-R75 exhibit only 28 per cent homology and their intracellular domains are devoid of any homology, indicating the likely existence of distinct signalling mechanisms. 

The exact molecular mechanisms by which TNF-induced signal transduction are mediated remain to be characterized in detail. Oligomerization of the receptors is often followed by their phosphorylation, most likely by accessory kinases that associate with the intracellular domain of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55 and TNF-R75 have also been established. Following clustering of the TNF receptors, these... 

The intact GM-CSF receptor is a heterodimer, consisting of a low-affinity a-chain and a P-chain, which also forms part of the IL-3 and IL-5 receptors. (The P-chain alone does not bind GM-CSF.) The a-chain is an 80 kDa glycoprotein and exhibits only a short intracellular domain. The larger P-chain (130 kDa) displays a significant intracellular domain. Signal transduction involves the (tyrosine) phosphorylation of a number of cytoplasmic proteins (Figure 10.2). 

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