3-Adrenergic receptors signal transduction

Hein L, KobiUca BK. Adrenergic receptor signal transduction and regulation. Neuropharmacology 1995 34 357-66. 

Figure 15.4. The p -Adrenergic Receptor Signal-Transduction Pathway. On binding of ligand, the receptor activates a G protein that in turn activates the enzyme adenylate cyclase. Adenylate cyclase generates the second messenger cAMP. The increase in cAMP results in a biochemical response to the initial signal.

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

The brain contains many other types of second-messenger-independent protein kinases. Examples of other second-messenger-independent protein kinases are listed in Table 23-1. Many of these include enzymes that were identified originally in association with a particular substrate protein but shown later to play a more widespread role in brain signal transduction. The functional role of one of these, [3-adrenergic receptor kinase (PARK), a type of G protein receptor kinase (GRK), is discussed further below. 

Fig. 3. Signal transduction of the tt2A-D79N adrenergic receptor. Mutation of the aspartic acid residue 79 in the second transmembrane domain of the mouse a2A adrenergic receptor to asparagine (D79N) selectively uncoupled this receptor mutant from activation of currents in vitro without interfering with Ca channel or adenylyl cyclase inhibition (Surprenant et al. 1992). In vivo, the a2A D79N receptor was expressed at 20% of the level of the wild-type a2A-receptor (MacMillan et d. 1996), and Ca channel inhibition was also blunted (a) (Lakhlani et al. 1997)...

Studies of peripheral NE receptor function have also shown alterations in a2 receptor and cyclic adenosine 39,59-monophosphate (cAMP) function in patients with PTSD. Decreases in platelet adrenergic a2-receptor number (Perry et al. 1987), platelet basal adenosine, isoproterenol, forskohn-stimulated cAMP signal transduction (Lerer et al. 1987), and basal platelet monoamine oxidase (MAO) activity (Davidson et al. 1985) have been found in PTSD. These findings may reflect chronic high levels of NE release which lead to compensatory receptor down-regulation and decreased responsiveness. 

E. J. M. Helmreich, T. Pfeuffer (1985). Regulation of signal transduction by P-adrenergic hormone receptors. Trends Pharmacol. Sci. 6 438-443. 

Hein P, Michel MC (2007) Signal transduction and regulation are all alphal-adrenergic receptor subtypes created equal Biochem. Pharmacol. 73 1097-1106. 

Hammond HK, Roth DA, Torsel PA, Ford CE, White FC, Maisel AS, Ziegler MG, Bloor CM, Insel PA. 1992. Myocardial beta-adrenergic receptor expression and signal transduction after chronic volume-overload hypertrophy and circulatory congestion. Circulation 85 269-280. 

Bohm, M., Zolk, O., Flesch, M., Schiffer, F., Schnabel, P., Stasch, J.P., and Knorr A. 1998a. Effects of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition on cardiac p-adrenergic signal transduction. Hypertension 31 747-754. 

Extracellular epinephrine (adrenaline) (from the adrenal medulla) activates /33-adrenergic receptors on fat cells to induce the breakdown of triacylglycerols to free fatty acids and glycerol. The intracellular enzyme involved in this process, hormone-sensitive lipase, is activated by protein kinase A. What are the key elements of the signal transduction cascade ... 

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