Clinical Box 42 Marijuana Antagonist Blocks Munchies

Agonist, antagonists, and partial agonists developed for G-protein-coupled receptors (GPCRs) have numerous clinical applications. Common examples associated with just the sympathetic nervous system include bi-adrenergic receptor antagonists (e.g., atenolol) used to slow heart rate and lower blood pressure, b2-adrenergic receptor agonists (e.g., albuterol) used as antiasthmatics, and a1-adrenergic antagonists (e.g., prazosin) used to lower blood pressure.

Recently, researchers have described cannabinoid (CB) receptors, which are the GPCRs that recognize tetrahydrocannabinol found in marijuana. The CB1 receptor is found in areas of the brain that control appetite and addiction to smoking (tobacco), and this receptor may be responsible for the "munchies" experienced by marijuana smokers. The munchie connection led researchers to develop CBi-receptor antagonists in hopes that they would be useful as aids for weight loss. One antagonist (rimonabant from Sanofi-Aventis) may soon be available as a diet pill and as an antismoking aid.

The phospholipase C (PLC) pathway. G-protein-coupled receptors (GPCRs) are coupled to G-proteins from several families, including Gs, Gi, Gq, and G12/13. Each of these G-protein families triggers different pathways. For example, binding to Gq can lead to activation of phospholipase C (PLC), an enzyme that increases cytosolic calcium through cleavage of the membrane phospholipid 4,5-bisphosphatidylinositol (Fig. 4.9). Cleavage of the lipid leads to release of inositol trisphosphate (IP3) and diacylglyc-erol (DAG). DAG remains associated with the membrane and is capable of activating protein kinase C (PKC). IP3 moves into the cytosol and binds to specific receptors on the endoplasmic reticulum (ER). Binding of IP3 opens a calcium channel, and the released calcium binds to calmodulin, a ubiquitous calcium sensor. Calmodulin undergoes a calcium-induced change in conformation that affects signaling in many



Target protein

Figure 4.9 Activation of the phosphatidylinositol (PI) signaling system by a G protein. Gqa activates PLC, an enzyme that can cleave the membrane lipid 4,5-bisphosphatidylinositol. Cleavage of the lipid releases two "second messengers," inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 releases calcium from the endoplasmic reticulum (ER) and triggers calmodulin-regulated pathways. DAG activates protein kinase C (PKC). For details, see Sec. 4.4.1, The phospholipase C (PLC) pathway.

pathways. Thus, activation of Gq initiates two separate signaling pathways that further diverge and converge to integrate cellular events.

As in the case of the cAMP pathway, every step in the signaling pathway involving PLC represents a highly controlled intersection in a complex cellular road map. Because calcium is a critical mediator in this pathway, lowering cytosolic calcium is one of the primary mechanisms for inhibiting signaling through the pathway. Cytosolic calcium is decreased primarily by sequestering it in the ER or by transporting it out of the cell. Sequestering and transport involve energy-requiring calcium "pumps" or calcium ATPases. Under resting conditions, pumps maintain cytosolic calcium at a concentration of 0.1 ^M which is approximately 1/10,000 of that in the extracellular fluid.

4.4.2 Protein-kinase-associated receptors

Protein-kinase-associated receptors may contain intrinsic kinase activity or the receptors associated directly with a kinase. By definition, protein kinases transfer phosphate groups from ATP to specific amino-acid residues in proteins. Tyrosine kinases (TKs) phosphorylate tyrosine residues while other kinases (e.g., PKA) primarily target serine and threonine residues. Many receptors ultimately activate protein kinases, including G-protein-coupled receptors (GPCRs) that indirectly activate kinases such as PKA and PKC.

One of the most extensively studied TK-associated receptor is the insulin receptor. The many pathways linked to insulin signaling are beyond the scope of this chapter, but two well-characterized pathways illustrate important aspects of protein-kinase-associated receptors.

The insulin receptor is a heterotetramer comprising two extracellular a-subunits and two transmembrane b-subunits (Fig. 4.10). Binding of insulin to the a-subunits activates TK activity associated with the intracellular portions of the b-subunits. Cross-phosphorylation between the b-subunits leads to phosphorylation of multiple tyrosine (Y) residues in the insulin receptor. The b-subunits also phosphorylate the adaptor protein insulin-receptor substrate (IRS) and other proteins.

Phosphorylated tyrosines (phosphotyrosines) serve as docking sites for proteins that bear an amino-acid sequence known as a Src homology 2 (SH2) domain. In Fig. 4.10, growth factor receptor-bound protein 2 (Grb2)

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