Coupling hormone receptor-effector

Receptors are proteins that bind specific hormones and generate an intracellular signal (receptor-effector coupling). 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Receptor-effector mechanisms include (1) enzymes with catalytic activities, (2) ion channels that gate the transmembrane flux of ions (ionotropic receptors), (3) G protein-coupled receptors that activate intracellular messengers (metabotropic receptors), and (4) cytosolic receptors that regulate gene transcription. Cytosolic receptors are a specific mechanism of many steroid and thyroid hormones. The ionotropic and metabotropic receptors are discussed in relevance to specific neurotransmitters in chapter 2. 

Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones for example, thyroid hormones increase both the number of 3 receptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a 3-adrenoceptor antagonist, in ameliorating symptoms of this disease. 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

In addition to factors, hormones, and neurotransmitters, known to act through receptors that couple to G proteins, Table I also lists effector systems that are or may be affected directly by activated G. Of these effector systems, positive and negative regulation of adenylyl cyclase, activation of phospholipases, activation of cGMP-PDE in photoreceptor cells, and activation of K+ channels are well docu-... 

Metabolic receptors - hormone and neurotransmitter receptors that are coupled to biochemical secondary messengers and effector mechanisms. Most metabolic receptors that are drug targets belong to the family of G protein-coupled receptors. 

Phospholipases of type Cfi function as effector enzymes in signal transmission by various G protein coupled receptors. The initiating external signals are diverse (see Fig. 5.16) and include hormones, neurohormones and sensory signals such as odorous agents and light (in nonvertebrates). 

Figure 13-11 Illustrates how G protein-coupled receptors transduce signals from extracellular hormones to associated effector proteins. Both the G, and G subunits are linked to the membrane by covalently attached lipids. In the resting state, when no ligand is bound to the receptor, the G subunit is bound to GDP and complexed with Gp. Binding of the normal hormonal ligand (e.g., epinephrine) or an ago-...

These are receptors for many hormones and neurotransmitters and are coupled to effector systems by a G-protein. 

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