Transmembrane enzymes, receptors

Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases... 

Examples of the actions of agonists can be taken from each of the two major molecular superfamilies. For the family of seven-transmembrane-region receptors linked to G proteins and enzymic second-messenger systems, the agonist would turn on the synthesis of second messenger to the greatest extent possible (i.e., the action... 

Enzyme receptors are transmembrane receptors with intrinsic enzymatic activity. Examples are the receptor tyrosine kinases (RTKs), which autophosphorylate their own tyrosine residues, such as the growth factor receptors and the insulin receptor. And, finally, there are the intracellular DNA sinding receptors. They bind lipophilic ligands that pass through the membrane. They address genes directly. Examples are the steroid hormone receptors (see Chapter 11). (This figure was donated by Professor Martin Lohse, University of Wurzburg.)... 

The mechanism of activation of the receptor-type guanylate cyclases is not entirely clear. As is the case with other single-transmembrane domain receptor types, such as receptor-type tyrosine kinases, some sort of dimerization may be induced by ligand binding, which serves to activate the intracellular enzyme part of the receptor. As discussed in the next section, dimerization is essential to enzyme activity in soluble guanylate cyclases. 

Drugs may act on intracellular receptors, membrane receptors directly coupled to ion channels, receptors linked via coupling proteins to intracellular effectors, receptors influencing cGMP and nitric oxide signaling, receptors that function as enzymes or transporters, receptors that function as transmembrane enzymes, or receptors for cytokines. 

Fig. 4.8. Major classes of drug receptors. (A) Transmembrane ligand-gated ion channel receptor. (B) Transmembrane G protein-coupled receptor (GPCR). (C) Transmembrane catalytic receptor or enzyme-coupled receptors. (D) Intracellular cytoplasmic/nuclear receptor. (From Simon JB, Golan DE, Tashjian A, Armstrong E, et al., eds. Chapter 1, Drug-Receptor Interactions. In Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy. Baltimore Lippincott Williams Wilkins, 2004, pp. 3-16, with permission.)...

After a brief overview of signal transduction, the text describes the structure of the seven-helix transmembrane P-adrenergic receptor and indicates how it transmits to the intracellular side of the plasma membrane a signal arising from binding the hormone epinephrine on the extracellular surface of the cell. The common features of the G proteins are presented next. The description of the information-transmission pathway from hormone stimulus to G proteins to adenylate cyclase is completed by a discussion of how cAMP activates specific protein kinases to modulate the activities of the phosphorylated target proteins. A small number of hormone molecules outside the cell results in an amplified response because each activated enzyme in the triggered cascade forms numerous products. There are many distinct seven-helix transmembrane hormone receptors. 

Protein tyrosine phosphatases. Phosphoprotein phosphatases are integral components of the signahng systems operated by protein kinases (Sun and Tonks, 1994). Cloning data show the protein tyrosine phosphatases (PTPs) to be a family of multidomain proteins having exceptional diversity. They can be broadly divided into two groups, the transmembrane or receptor-like PTPs and the cytosolic PTPs. None of these are related to the serine-threonine specific phosphatases. This is in contrast to the protein kinases (Seer-Thr and Tyr specific), which share a common ancestry. Unlike the Ser-Thr phosphatases, in which substrate specificity is determined by associated targeting subunits, the Tyr phosphatases are all monomeric enzymes. 

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