Noradrenergic Receptors

The division of adrenoceptors into a- and p-types emerged some 50 years ago and was based on the relative potencies of catecholamines in evoking responses in different peripheral tissues. Further subdivision of p-adrenoceptors followed characterisation of their distinctive actions in the heart (pi), where they enhance the rate and force of myocardial contraction and in the bronchi (p2), where they cause relaxation of smooth muscle. The binding profile of selective agonists and antagonists was the next criterion for classifying different adrenoceptors and this approach is now complemented by molecular biology. The development of receptor-selective ligands has culminated in the characterisation of three major families of adrenoceptors (a1, a2 and p), each with their own subtypes (Fig. 8.10). All these receptors have been cloned and belong to the superfamily of G-protein-coupled receptors predicted to have seven transmembrane domains (Hieble, Bondinell and Ruffolo 1995; Docherty 1998).

The a1-subgroup is broadly characterised on the basis of their high affinity for binding of the antagonist, prazosin, and low affinity for yohimbine but they seem to be activated to the same extent by catecholamines. There are at least three subtypes which for historical reasons (Hieble, Bondinell and Ruffolo 1995) are now designated a1A, a1B and a1D. a1A-Adrenoceptors are distinguished by their selective antagonists tamsulosim

Figure 8.10 Subdivisions of a- and p-adrenoceptor families

and WB4101 but, whereas a1B- and a1D-adrenoceptors have ligands that distinguish them from a1A-adrenoceptors, and from each other, these ligands bind to other transmitter receptors and so they are not really selective. An alternative classification (also based on sensitivity to prazosin) characterised two classes of receptor: a1H and a1L receptors. Whereas those classified as a1H seem to overlap with a1A, a1B and a1D receptors (and are now regarded as the same), there is no known equivalent of the a1L receptor. Although it is still tentatively afforded the status of a separate receptor, it has been suggested that it is an isoform of the a1A subtype (Docherty 1998).

All ^-adrenoceptors are coupled to the Gq/11 family of G-proteins and possibly other G-proteins as well. When activated, they increase the concentration of intracellular Ca2+ through the phospholipase C/diacyl glycerol/IP3 pathways (Ruffolo and Hieble 1994) but other routes have been suggested too. These include: direct coupling to Ca2+ (dihydropyridine sensitive and insensitive) channels, phospholipase D, phospholipase A2, arachidonic acid release and protein kinase C. Their activation of mitogen-activated protein (MAP) kinase suggests that they also have a role in cell proliferation. All three subtypes are found throughout the brain but their relative densities differ from one region to another. A detailed review of the classification of ^-adrenoceptors is to be found in Zhong and Minneman (1999).

^-Adrenoceptors all have a high affinity for yohimbine (although there are species differences) and are negatively coupled to a Pertussis toxin-sensitive Gi/o-protein in some tissues whereas, in others, they appear to be insensitive to this toxin. Their activation inhibits target cell activity, resulting from reduced cAMP production, an increase in K+ current and a reduced Ca2+ current. However, stimulatory effects of a2-adrenoceptors have also been reported, although the underlying mechanisms are unclear. Paradoxically, the different receptor subtypes are characterised by their affinity for prazosin: the a2A-subtype (found in human platelets) has a low affinity for this ligand, while the a2B-subtype (isolated from neonatal rat lung) has a higher affinity. The a2C-adrenoceptor, first isolated from opossum kidney (OK) cells, is distinguished by its characteristic relative affinities for yohimbine and prazosin. There is also functional evidence for an a2D-adrenoceptor. This has not been granted the status of a separate subtype, partly because it has not been possible to produce a distinctive receptor clone, and it is now regarded as the rodent homologue of the human a2A-subtype. (Bylund et al. 1994).

It is the a2A/D-adrenoceptor that predominates in the locus coeruleus and this subtype seems to be responsible for reducing neuronal excitability and transmitter release. Strangely, immunocytochemical studies suggest that most a2C-receptors are intracel-lular. The explanation for this finding and its functional implications are as yet unknown but it could reflect differences in intracellular trafficking of different receptor subtypes.

Contrasting with the ^-adrenoceptors, ¿-adrenoceptors activate cAMP synthesis and are coupled to Gs-proteins. The S and ¿S2 subtypes were distinguished in the 1960s but the ^-adrenoceptor has been characterised only recently, largely on the basis of its low affinity for the antagonist, propranolol. Unlike ¿Sr and ^-adrenoceptors, this subtype is not found in the brain but probably has an important role in lipolysis by mobilising triglyceride stores and promoting thermogenesis (Giacobino 1995).

In the brain, autoradiography has shown that ¿1- and ^-adrenoceptors have quite distinct distributions. Thus, approximately 60% of the ¿-adrenoceptors in the neocortex are of the ^-subtype while, in the cerebellum, it is the ¿S2-subtype that predominates. As yet, the functional implications of this uneven distribution are unclear and await the development of more subtype selective agents. However, unlike the a-adrenoceptor families, the affinity of catecholamines for ^-adrenoceptors differs markedly: noradrenaline is a relatively weak agonist at the ^-subtype whereas it is more potent than adrenaline at ^-receptors.

Electrophysiological studies of the ^-adrenoceptor have produced complex findings. In cardiac tissue, their activation leads to an increase in Ca2+ conductance and so they are regarded as excitatory receptors. ^-Adrenoceptor activation in cortical pyramidal cells causes an increase in excitability mediated by a reduction of a Ca2+-activated K+ current. A different response is evoked in thalamic relay neurons where these receptors cause depolarisation and an increase in input conductance by resetting a hyperpolar-isation-induced cation current. In the dentate gyrus their activation causes an increase in voltage-dependent Ca2+ currents through opening of Ca2+ channels.

Because of these disparate findings, it is difficult to assign particular electro-physiological changes to each of the adrenoceptors let alone to noradrenaline, more generally. A shortage of selective ligands aggravates this problem. Another difficulty concerns the uncertain location of the receptors responsible for initiating any changes. In tissue slices, the target receptors could be located on interneurons, rather than mediating direct axo-somatic interactions, for instance. The net effect of receptor activation could also depend on the underlying tonic activity of the target cell as well as the influence of other neurotransmitters that converge on the same G-protein.

Despite these obstacles, it has been suggested that the overall effect of interactions between noradrenaline and its receptors could be to increase the excitability and responsiveness of the target cells. This could make an important contribution to the governance of arousal and selective attention (McCormick, Pape and Williamson 1991). Another, similar suggestion is that noradrenergic transmission increases the signal-to-noise ratio of cell responses to incoming stimuli: i.e. it reduces the basal activity of target cells but increases their response to excitatory inputs. This is the so-called 'Kety hypothesis' (reviewed by Harley 1987).

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