Impact Of Ne On Target Structures A The Variety of Noradrenergic Receptors

Adrenoreceptors are membrane-bound, G-protein-coupled receptors located throughout the body on neuronal and nonneuronal tissues, where they mediate a diverse range of responses to NE and epinephrine. They share the common features of an extracellular amino terminus, seven transmembrane domains, and an intracellular carboxy terminus.

1. Adrenoreceptor Classification

The adrenoreceptor family was initially divided into two subtypes, the a- and b-adrenoreceptors, as first proposed in 1948 by Raymond Ahlquist, an American pharmacologist. A quarter of a century later, the a-adrenoreceptors were further subdivided by Langer according to their anatomical location, with a-adre-noreceptors located on sympathetic nerve terminals designated as a2-adrenoreceptors and those located postsynaptically designated as a1-adrenoreceptors. This anatomical classification rapidly gave way to the identification of pharmacological differences between a-adrenoreceptors, notably, the ability of yo-himbine and rauwolscine to act as a2-adrenoreceptor antagonists. Subsequent studies using pharmacological and molecular biological techniques have further subdivided the a-adrenoreceptor family; three subtypes within each group have now been cloned and pharmacologically characterized. The al-adrenorecep-tor subtypes have been classified as the a1A-, a1B-, and a1D-adrenoreceptors, and the a2-adrenoreceptors have been classified as a2A-, a2B-, and a2C-adrenor-eceptors (see Fig. 6).

a. a1-Adrenergic Receptors Subdivision of the al-adrenoreceptors has been facilitated by both pharmacological and molecular biological techniques. The initial classification of a1-adrenoreceptors as a1A and a1B subtypes was determined from differences in the binding characteristics of the competitive antagonist WB 4101 and a site-directed alkylating agent, chlor-oethylclonidine (CEC). In addition, three different cDNAs, which coded for a1 subtypes, were isolated. These have since been characterized and are believed to code for three functional a1-adrenoreceptors: the a1A and a1B subtypes as described earlier and a third subtype, the a1D. A putative a1L-adrenoreceptor shows characteristics similar to those of the a1A- and a1D-adrenoreceptors, but the gene has not been identified.

The a1-adrenoreceptors mediate their response via the Gq/l1 mechanism. All of the subtypes are coupled to phospholipase C, and activation of the receptor results in the production of inositol triphosphate (IP3) and diacylglycerol (DAG). The production of these second messengers results in the activation of both

Figure 6 Adrenergic receptor classification. Adrenergic receptors are divided into al-, a2-, and b-adrenoreceptors. These categories are further subdivided into subtypes, for which genes have been identified. al-Adrenorecptors are coupled to the G-protein Gq/11, which activates the phospholipase C, producing inositol triphosphate (IP3) and diacylglycerol (DAG). a2-Adrenoreceptors are coupled to the G-protein Gi/Go Which inhibits cyclic adenosine monophosphate (cAMP) production by adenylyl cyclase. b-Adrenoreceptors are coupled to the G-protein Gs, which stimulates adenylyl cyclase production of cAMP.

Figure 6 Adrenergic receptor classification. Adrenergic receptors are divided into al-, a2-, and b-adrenoreceptors. These categories are further subdivided into subtypes, for which genes have been identified. al-Adrenorecptors are coupled to the G-protein Gq/11, which activates the phospholipase C, producing inositol triphosphate (IP3) and diacylglycerol (DAG). a2-Adrenoreceptors are coupled to the G-protein Gi/Go Which inhibits cyclic adenosine monophosphate (cAMP) production by adenylyl cyclase. b-Adrenoreceptors are coupled to the G-protein Gs, which stimulates adenylyl cyclase production of cAMP.

voltage-dependent and -independent calcium channels, as well as protein kinase C and phospholipase A2 and D stimulation, arachidonic acid release, and cyclic AMP formation.

The a1-adrenoreceptors are located in both the central and peripheral nervous systems. In the CNS, they are predominantly located postsynaptically where they mediate an excitatory response and are particularly concentrated in the anterior cerebral cortex and thalamus. Peripheral a1-adrenoreceptors are located on both vascular and nonvascular smooth muscle, where their activation results in contraction. On the vascular smooth muscles, the a1-adrenoreceptors are located intrasynaptically where they mediate the response to endogenous neurotransmitter release. They are also located in the heart, where they mediate a positive ionotropic effect, and in the liver, where they activate glycogen phosphorylation.

b. a2-Adrenergic Receptors The a2-adrenorecep-tors are located on both pre- and postsynaptic neurons, where they mediate an inhibitory role on the central and peripheral nervous systems. The heterogeneous nature of the a2-adrenoreceptor was first determined from the different pharmacological profiles of the receptor between species, and subsequent studies have revealed the presence of different subtypes within the same tissue. Thus, on the basis of radioligand binding profiles, amino acid sequence, and chromosomal location, four distinct subtypes of a2-adrenoreceptor have been characterized. These a2-adrenoreceptor subtypes, a2A, a2B, a2C, and a2D, are found in a variety of species and tissues and have been characterized by using tissue and cell lines expressing only one subtype. The a2D subtype exhibits a distinct pharmacological profile, but from the sequence homology it is believed to be a species variation of the a2A subtype and is not recognized as separate.

a2-Adrenoreceptors mediate their functions through a variety of G-proteins including G; and Go. All of the subtypes have been shown to be negatively coupled to adenylyl cyclase and to mediate an inhibitory effect through the inhibition of cyclic AMP production. In addition, evidence now links the a2-adrenoreceptors to the stimulation of Ca2 + influx and also the activation of K+ channels, phospholipase A2, and Na+-H+ exchange.

a2-Adrenoreceptors are found in both the central and peripheral nervous systems, located either pre- or postsynaptically. In the CNS, this receptor can regulate neurotransmitter release as an autoreceptor when located on noradrenergic nerve terminals or as a heteroreceptor when bound on nonnoradrenergic nerve terminals. This role in regulating the release of both NE and serotonin has stimulated the investigation and development of a2-antagonists such as idazoxan in order to cure mental depression.

c. b-Adrenergic Receptors The b-adrenoreceptors were first subdivided into b1- and b2-adrenoreceptors following comparison of the rank order of potency of various adrenergic agonists. The b1-adrenoreceptor is predominant in the heart and adipose tissue and displays equal affinity for epinephrine and NE. In contrast, the b2-adrenoreceptor is predominant on vascular, uterine, and airway smooth muscle and exhibits a higher selectivity for NE than epinephrine.

The classification of b-adrenoreceptors is not limited to b1- and b2-adrenoreceptors. Characterization of b-adrenoreceptor-mediated responses resulted in evidence for further atypical subtypes, b3 and b4, which are insensitive to typical b-adrenergic antagonists. The b4-adrenoreceptor is localized in the cardiac tissue.

The b1-adrenoreceptor is positively coupled to the adenylyl cyclase via activation of Gs. b2- and b3-adrenoreceptors are also coupled to Gs, but their activation can result in either the stimulation or inhibition of adenylyl cyclase. Activation of the b4-adrenergic receptor results in increased cyclic AMP and the stimulation of cyclic-AMP-pendent protein kinase. There is also evidence to suggest that b-adrenoreceptors are linked to voltage-gated Ca2+ channels.

The b1- and b2-adrenorecetors have distinct patterns of distribution in the CNS, as determined by using in situ hybridization. In the rat, b1-adrenor-eceptors are found in high densities in the striatum, although there is an almost complete absence of noradrenergic innervation in that structure, whereas the highest brain concentration of b2-adrenoreceptors is found in the cerebellum.

2. Adrenoreceptor Desensitization and Resensitization

A regulatory feature shared by many of the members of the superfamily of G-protein-coupled receptors is that of desensitization. In response to prolonged or repeated agonist exposure, dampening of the signal transduction process is observed. Desensitization represents the summation of several different processes, including receptor phosphorylation, receptor sequestration, enhanced degradation of intracellular messengers, and degradation of receptor protein.

Rapid receptor desensitization appears to be mediated by uncoupling of the receptor from its respective G-protein, a consequence of receptor phosphoryla-tion. This mechanism has been studied particularly for the b2-adrenoreceptor, which is phosphorylated on serine and threonine sites by PKA or PKC (Fig. 7A).

b2-Adrenoreceptors are also phosphorylated by b-adrenergic receptor kinase (b-ARK), a member of the G-protein-coupled receptor kinase (GRK) family (Fig. 7B). GRKs are kinases specialized in receptor desensitization. After phosphorylation by GRKs, receptors are recognized by cytosolic proteins from the arrestin family, and binding of arrestin proteins blocks the activation of the G-protein. Once uncoupled from the G-protein, the receptor function can only be restored by receptor dephosphorylation. The extent and duration ofreceptor desensitization depend not only on the activity of GRKs but also on the activity of the G-protein-coupled receptor phospha-tases (GRP). b2-Adrenergic receptor uncoupling is rapidly followed by sequestration into an intracellular compartment distinct from the plasma membrane. The low pH in these endocytosis vesicles induces a conformational change in the receptor, allowing dephosphorylation by GRP. Once dephosphorylated, the receptors are recycled back to the plasma membrane.

Although it has been studied particularly for b-adrenergic receptors, desensitization also occurs for a-adrenergic receptors; b1-adrenergic and a2-adrenergic receptor desensitization has been proposed as a mechanism of action of chronic antidepressant treatment.

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