Enzymes membrane-spanning, receptors

Receptors for ADP, epinephrine, thromboxane, thrombin and PAF have been well characterized (27, 31, reviewed in other chapters). Membrane spanning receptors of epinephrine, t mbin and thromboxane are coupled to the ubiquitous GTP-hinding proteins. Platelets contain monomeric, low molecular weight G proteins as well as heterotrimeric membrane associated G roteins. GTP binding to e a-subunit of G-proteins fiicilitates die interaction with effector enzymes, resulting in the hydrolysis of GTP to GDP, which terminates its stimulatory role (29). 

Figure 1.10 Model of a G protein-coupled receptor with 7 membrane-spanning domains. Binding of an agonist to the receptor causes GDP to exchange with GTP. The a-GTP complex then dissociates from the receptor and the py complex and interacts with intercellular en mes or ion channels. The Py complex can activate an ion channel or possibly also interact with intercellular enzymes. GDP, guanine diphosphate GTP, guanine triphosphate cAMP, cyclic adenosine monophosphate PKC, protein kinase C PLC, phospholipase C DAG, diacylglycerol.

Fig. 14.5 The TCR Complex is associated with a number of T< ll specific membrane-spanning proteins.31 The antigen receptors and the co-receptors, CDS, CD4, and CDS, together with associated enzymes, tyrosine kinases and phosphatases, form the actual signalling complex. The cytoplasmic chains of the co-receptor molecules have characteristic consensus sequences, the ITAMs (immunoreceptor tyrosine activation motife). Each of the invariant -chains and the CD3-y,8, e chains, contain 1-3 copies of the RAM motife. The structure of the TCR-signalling complex still needs to be clarified.

The adenylate cyclase enzyme that is activated by the epinephrine-P-adrenergic receptor complex is a membrane protein that contains 12 presumed membrane-spanning helices. The enzymatically active part of the protein is formed from two large intracellular domains one is located between transmembrane helices 6 and 7 and the other after the last... 

Receptors located on membrane-spanning enzymes Drugs that affect membrane-spanning enzymes combine with a receptor on the extracellular portion of enzymes and... 

Insulin receptors. Iti.suLin receptors are membrane-spanning glyco-proieins consisting of two a-siibimits and two fl-subunits linked cova-Icnily by disulphide bonds. After insulin binds to the u-subuntt. the insulin-receptor complex enters the cell, where the insulin is destroyed hy lysosomal enzymes. The internalization of the insulin-receptor complex underlies the (iown-re)(ulan(jii of receptors that is produced hy high levels of insulin (e.g. in obese subjects). The binding of insulin to the receptors activate.s the tyrosine kinase activity of the p-subunii and initiates a complex chain of reactions that lead to the effecLs of insulin. 

A considerable array of small molecules of biological importance make use of cation-n interactions when binding to their protein targets. A well-documented example is the neurotransmitter acetylcholine (ACh). At two different binding sites — acetylcholine esterase (AChE), the enzyme that terminates synaptic transmission by hydrolyzing ACh and the nicotinic acetylcholine receptor (nAChR), a prototype membrane-spanning neuroreceptor involved in synaptic transmission—the quaternary ammonium ion of ACh makes close contact with a Trp side chain. Note that this was anticipated by earlier cyclophane studies. 

Helix receptors (left) are proteins that span the membrane with only one a-helix. On their inner (cytoplasmic) side, they have domains with allosterically activatable enzyme activity. In most cases, these are tyrosine kinases. 

Water-soluble peptide and amine hormones (insulin and epinephrine, for example) act extracellularly by binding to cell surface receptors that span the plasma membrane (Fig. 23-4). When the hormone binds to its extracellular domain, the receptor undergoes a conformational change analogous to that produced in an allosteric enzyme by binding of an effector molecule. The conformational change triggers the downstream effects of the hormone. 

Today, we realize that drug binding/receptor sites that produce pharmacological effects may be part of any cellular constituent for example, nuclear DNA, mitochondrial enzymes, ribosomal RNA, cytosolic components, and cell membranes and wall, to name the most obvious. Nevertheless, in contemporary pharmacology, some authors and researchers apply a more restricted use of the term receptor, reserving it for protein complexes embedded in, and spanning, cellular membranes. However, exceptions to this classification system clearly exist. For example, steroids are known to interact with cytosolic receptors that transport them into the nucleus (their site of... 

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