Adrenergic receptor second messengers

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. 

Adrenergic receptors These are membrane bound G-protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers cAMP or inositol triphosphate (IP3)/diacyl glycerol (DAG). Adrenergic receptors are classified into two main groups [Pg.131]

Another second messenger system, the inositol triphosphate-diacylglycerol system, can also be activated by cholinergic or adrenergic receptors. It involves calcium movement and will be discussed when and if time permits. 

Receptor proteins (serpentine receptors) that indirectly activate (through GTP-binding proteins, or G proteins) enzymes that generate intracellular second messengers. This is illustrated by the /3-adrenergic receptor system that detects epinephrine (adrenaline) (Section 12.4). 

The / -Adrenergic Receptor System Acts through the Second Messenger cAMP... 

The /3-adrenergic receptor binds epinephrine, then through a stimulatory G protein, Gs, activates adenylyl cyclase in the plasma membrane. The cAMP produced by adenylyl cyclase is an intracellular second messenger that stimulates cAMP-dependent protein kinase, which mediates the effects of epinephrine by phosphorylating key proteins, changing their enzymatic activities or structural features. 

All of the effects of the catecholamines bound to (3 adrenergic receptors and of glucagon, ACTH, and many other hormones appear to be mediated by adenylate cyclase. This integral membrane protein catalyzes the formation of cAMP from ATP (Eq. 11-8, step a). The reaction, whose mechanism is considered in Chapter 12, also produces inorganic pyrophosphate. The released cAMP acts as the second messenger and diffuses rapidly throughout the cell to activate the cAMP-dependent protein kinases and thereby to stimulate phosphorylation of a selected group of proteins (Fig. 11-4). Subsequent relaxation to a low level of cytosolic cAMP is accomplished by hydrolysis of the cAMP by a phosphodiesterase (Eq. 11-8, step fr).166/167 jn thg absence of phosphodiesterase cAMP is extremely stable kinetically. However, it is thermodynamically unstable with respect to hydrolysis. 

One example of this is the super-family of receptors organized with seven transmembrane regions (Fig. 2—3). This is a structure common to many neurotransmitter receptors that use second-messenger systems and are slow in responding (e.g., serotonin-2A receptors and beta-2 adrenergic receptors). A description of the seven-transmembrane region superfamily of receptors will be amplified below in our discussion of receptors linked to second-messenger systems. 

Answer A hormone can be degraded by extracellular enzymes (such as acetylcholinesterase). The GTP bound to a G protein can be hydrolyzed to GDP. A second messenger can be degraded (cAMP, cGMP), further metabolized (IP3), or resequestered (Ca2 +, in the endoplasmic reticulum). A receptor can be desensitized (acetylcholine receptor/channel), phosphorylated/inactivated, bound to an arrestin, or removed from the surface ( -adrenergic receptor, rhodopsin). 

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