Signal Transduction Pathways of PAdrenoceptors

P-ARs are coupled by Gs to adenylate cyclase and produce alterations in cellular activity by raising intracellular levels of cyclic AMP (Fig. 3). Pharmacologically, the classical P-ARs have been defined as receptors at which (-)-isoprenaline acts as an agonist and (-)-propranolol as an antagonist. In addition to the classical P1- and P2-ARs there is a third subtype, the P3-AR,

Figure 1. Signal transduction pathways for aj-adrenocceptors. Gq/jj couples aj-adrenenoceptor to PIP2 (phosphatidyl inositol bisphosphate). The interaction of the G-protein activates phospholipase C-depen-dent hydrolysis of PIP2. This generates the second messengers inositol trisphosphate (IP3) which releases calcium from the intracellular stores of the sarcoplasmic reticulum (SR), and diacylglycerol (DAG), which activates protein kinase C (PKC). This can lead to further interactions with other second messenger dependent protein kinases such as RAS and MAP kinases.

Figure 1. Signal transduction pathways for aj-adrenocceptors. Gq/jj couples aj-adrenenoceptor to PIP2 (phosphatidyl inositol bisphosphate). The interaction of the G-protein activates phospholipase C-depen-dent hydrolysis of PIP2. This generates the second messengers inositol trisphosphate (IP3) which releases calcium from the intracellular stores of the sarcoplasmic reticulum (SR), and diacylglycerol (DAG), which activates protein kinase C (PKC). This can lead to further interactions with other second messenger dependent protein kinases such as RAS and MAP kinases.

Figure2. Signal transduction pathways for a2-adrenoceptors. Activation of a2-adrenoceptors causes Gi to inhibit adenylate cyclase leading to a decrease in cAMP levels.

which has been detected in the brain72 and is characterized by distinct pharmacology and a short C-terminal region that lacks phosphorylation sites. Unlike the Pi- and P2-AR, P3-ARs are resistant to desensitisation involving phosphorylation. There are now highly selective compounds that delineate P1-, P2- and P3-ARs.

During time periods of minutes to hours, phosphorylation of the P2-AR is closely involved in desensitisation. Agonist occupied receptors are substrates for phosphorylation by G-protein

Figure3. Signal transduction pathways for ^-adrenoceptors. Activation of ^-adrenoceptors couples the receptor to Gs and activates adenylate cyclase increasing cAMP levels within the cell. cAMP activates the kinase PKA leading to phosphorylation and desensitisation of the ^-adrenoceptor.

receptor kinases. Phosphorylated receptors uncouple from the signal transduction pathway but are also substrates for P-arrestin, an adaptor protein involved in pinocytosis and subsequent internalisation of receptor complexes. Internalised receptors may undergo proteolysis or be dephosphorylated and re-inserted in the plasma membrane. Receptor phosphorylation by PAR kinases involves Ser and Thr residues in the carboxy-terminus region. The shorter C-termi-nus region of the P3-AR contains few potential phosphorylation sites, which may be the reason that this receptor does not down-regulate in response to prolonged agonist stimulation.

The second messenger systems are also capable of interacting with other kinases such as the CAM kinase and MAP kinase pathways all of which have been implicated in long-term memory formation (see Medina and Cammarota, and also Selcher et al in this book).

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