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Am J Physiol Regul Integr Comp Physiol 283: R287-R295, 2002; doi:10.1152/ajpregu.00123.2002
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Vol. 283, Issue 2, R287-R295, August 2002

INVITED REVIEW
Physiological significance of alpha 2-adrenergic receptor subtype diversity: one receptor is not enough

Melanie Philipp, Marc Brede, and Lutz Hein

Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
BLOOD PRESSURE REGULATION
ANALGESIA
SEDATION
BEHAVIOR
OTHER PHYSIOLOGICAL FUNCTIONS...
CONCLUSIONS
REFERENCES

alpha 2-Adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of alpha 2-adrenergic receptors, alpha 2A, alpha 2B, alpha 2C, have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual alpha 2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting alpha 2-receptor subtypes, e.g., alpha 2A-receptors decrease sympathetic outflow and blood pressure, whereas the alpha 2B-subtype increases blood pressure. Other biological functions are regulated by synergistic alpha 2-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, alpha 2A and alpha 2C. Similarly, nociception is controlled at several levels by one of the three alpha 2-receptor subtypes. Further investigation of the specific function of alpha 2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.

adrenergic receptors; transgenic mice; gene targeting


    INTRODUCTION
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ABSTRACT
INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
BLOOD PRESSURE REGULATION
ANALGESIA
SEDATION
BEHAVIOR
OTHER PHYSIOLOGICAL FUNCTIONS...
CONCLUSIONS
REFERENCES

ADRENERGIC RECEPTORS FORM the interface between the endogenous catecholamines epinephrine and norepinephrine and a wide array of target cells in the body to mediate the biological effects of the sympathetic nervous system. To date, nine distinct adrenergic receptor subtypes have been cloned from several species: alpha 1A, alpha 1B, alpha 1D, alpha 2A, alpha 2B, alpha 2C, beta 1, beta 2, and beta 3 (11). For many of these receptors, their precise physiological functions and their therapeutic potential have not been fully elucidated. Only for beta -adrenergic receptors have sufficiently subtype-selective ligands been developed that have helped to identify the physiological significance of beta 1-, beta 2-, and beta 3-receptors, some of which have entered clinical medicine. Selective agonists for the beta 2-adrenergic receptor play an important role in asthma therapy, whereas beta 1-receptor antagonists are first-line medication for patients with hypertension, coronary heart disease, or chronic heart failure (8, 20, 50). For alpha 1-receptors, subtype-selective ligands that can diminish the symptoms of benign prostate hyperplasia without causing hypotension have just entered clinical therapy (33). Despite the fact that alpha 2-adrenergic receptors serve a number of physiological functions in vivo and have great therapeutic potential, no sufficiently subtype-selective ligands are clinically available yet. Despite this fact, non-subtype-selective alpha 2-receptor agonists like clonidine, medetomidine, and brimonidine are being used to treat patients with hypertension, glaucoma, tumor pain, postoperative pain, and shivering or to block the symptoms of sympathetic overactivity during drug withdrawal (66). Unfortunately, the fields of therapeutic application and unwanted side effects are overlapping, e.g., alpha 2-receptor-mediated sedation is an important problem for treatment of hypertension. Severe side effects are one reason why alpha 2-receptor agonists are only second-line antihypertensive agents. It is tempting to speculate that alpha 2-receptor-mediated therapy could be greatly improved and advanced if receptor subtype-selective ligands were available. However, before developing specific ligands, the therapeutic targets have to be identified. Recently, transgenic and gene-targeted mouse models have added considerable information about individual adrenergic receptor subtypes (15, 25, 37, 39, 53, 54). This review focuses on the specific functions of the three alpha 2-adrenergic receptor subtypes in mouse models carrying targeted deletions in the genes encoding for alpha 2-receptors.


    alpha 2-ADRENERGIC RECEPTOR GENES
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ABSTRACT
INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
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So far, three distinct genes have been identified from several species that encode for separate subtypes of alpha 2-adrenergic receptors (11). From these genes, three alpha 2-receptors are synthesized, termed alpha 2A, alpha 2B, and alpha 2C. The pharmacological ligand binding characteristics of the alpha 2A-subtype differ significantly between different species, thus giving rise to the pharmacological subtypes alpha 2A in humans, rabbits, and pigs and alpha 2D in rats, mice, and guinea pig (11). This species variation is at least in part due to a single amino acid variation in the fifth transmembrane domain of the alpha 2A-receptor that renders this receptor less sensitive to yohimbine binding (34).


    GENE-TARGETED MICE LACKING INDIVIDUAL alpha 2-RECEPTOR SUBTYPES
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Several mouse lines have been established by gene targeting that do not express functional alpha 2-adrenergic receptors (2, 35, 36). All of these mice developed apparently normally, although mice lacking alpha 2B-adrenergic receptors were not born at the expected Mendelian ratios, indicating that this receptor may play a role during embryonic development (13, 35).

In addition, a point mutation has been introduced into the alpha 2A-receptor gene (alpha 2-D79N) to evaluate the physiological role of separate intracellular signaling pathways of this receptor in vivo (38). The D79N mutation substitutes asparagine for an aspartate residue at position 79, which is predicted to lie within the second transmembrane region of the alpha 2A-receptor and is highly conserved among G protein-coupled receptors. In vitro, the alpha 2A-D79N receptor has been shown to be deficient in coupling to K+ channel activation (76). However, in vivo this point mutation was found to be deficient in K+ current activation and Ca2+ channel inhibition (32). Surprisingly, the density of alpha 2A-D79N receptors in the mouse brain was decreased to ~20% of the normal level (38). Thus, in most (but not all) functional tests, the alpha 2A-D79N receptor had characteristics resembling a functional "knockout" of the alpha 2A-receptor (40). One important exception was the observation that the presynaptic inhibitory function of the alpha 2A-D79N receptor was normal or only slightly blunted in intact tissues (2). Most likely, the decreased expression of alpha 2A-D79N receptors in vivo rather than a selective defect in receptor signaling seems to be important for the "functional knockout." At the presynaptic side, a high number of spare receptors is characteristic for alpha 2-receptor function, i.e., activation of very few alpha 2-receptors results in maximal presynaptic inhibition of transmitter release (1). Thus the reduced number of presynaptic alpha 2A-D79N receptors may still be sufficient for presynaptic control, whereas the decreased receptor density may compromise receptor signal transduction at other sites with a smaller receptor reserve.


    WHICH alpha 2-RECEPTOR SUBTYPE IS THE PRESYNAPTIC REGULATOR?
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WHICH alpha 2-RECEPTOR SUBTYPE IS...
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alpha 2-Adrenergic receptors were initially characterized as presynaptic receptors that serve as parts of a negative feedback loop to regulate the release of norepinephrine (71). Soon it was shown that alpha 2-receptors are not restricted to presynaptic locations but also have postsynaptic functions (Fig. 1A). With the use of an array of pharmacological antagonists, the alpha 2A-receptor was predicted to be the major inhibitory presynaptic receptor regulating release of norepinephrine from sympathetic neurons as part of a feedback loop (82). However, in some tissues, the alpha 2C-receptors were considered to be in the inhibitory presynaptic receptor (55).


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  		Fig. 1.   Presynaptic alpha 2-adrenergic receptor subtypes. A: in sympathetic or central adrenergic nerves, alpha 2A- and alpha 2C-receptors operate as inhibitory autoreceptors to control neurotransmitter release. alpha 2B-Receptors are located on postsynaptic cells to mediate the effects of catecholamines released from sympathetic nerves, e.g., vasoconstriction. B: presynaptic alpha 2A- and alpha 2C-receptors can be distinguished functionally. In intact tissue slices from mouse heart atria, alpha 2A-receptors inhibit norepinephrine release from sympathetic nerves primarily at high stimulation frequencies, whereas the alpha 2C-receptor can also operate at very low frequencies to control basal norepinephrine release. WT, wild type. Data adapted from Ref. 26.

With the genetic deletion of individual alpha 2-receptor genes in mice, this classification of the presynaptic autoreceptor subtype was challenged. In mice lacking the alpha 2A-subtype, presynaptic feedback regulation was severely impaired but not abolished, indicating that indeed the alpha 2A-receptor is the major autoreceptor in sympathetic neurons (Fig. 1A) (2, 26). Most surprisingly, the alpha 2C-receptor turned out to function as an additional presynaptic regulator in all central and peripheral nervous tissues investigated (Fig. 1A) (2, 9, 26, 70, 79, 80). However, the relative contributions of alpha 2A- and alpha 2C-receptors differed between central and peripheral nerves, with the alpha 2C-receptor being more prominent in sympathetic nerve endings than in central adrenergic neurons. alpha 2A- and alpha 2C-receptors differ in their time course of expression after birth (65). While alpha 2A-mediated autoinhibition of neurotransmitter release is already operative immediately after birth, the alpha 2C-receptor function is established later in mice (65).

Furthermore, the alpha 2-autoreceptor subtypes could be distinguished functionally: alpha 2A-receptors inhibited transmitter release significantly faster and at higher action potential frequencies than the alpha 2C-receptors (Fig. 1B) (9, 26, 62). When alpha 2A- and alpha 2C-receptors were stably expressed together with N-type Ca2+ channels or with G protein-coupled inwardly rectifying K+ (GIRK) channels, no differences in the activation kinetics of these two receptor subtypes were detected at identical levels of receptor expression (10). However, when receptor GIRK channel deactivation after removal of norepinephrine was followed, the alpha 2C-receptor was found to be active for a significantly longer time than the alpha 2A-subtype irrespective of the level of receptor expression. This difference in alpha 2-receptor deactivation kinetics could be explained by the higher affinity of norepinephrine for the alpha 2C- than for the alpha 2A-receptor subtype (10). This property makes the alpha 2C-receptor particularly suited to control neurotransmitter release at low action potential frequencies (Fig. 1) (26). In contrast, the alpha 2A-receptor seems to operate primarily at high stimulation frequencies in sympathetic nerves and may thus be responsible for controlling norepinephrine release during maximal sympathetic activation.

alpha 2-Adrenergic receptors not only inhibit release of their own neurotransmitters (autoreceptors) but can also regulate the exocytosis of a number of other neurotransmitters in the central and peripheral nervous system. In the brain, alpha 2A- and alpha 2C-receptors can inhibit dopamine release in basal ganglia (9) as well as serotonin secretion in mouse hippocampal or brain cortex slices (61). In contrast, the inhibitory effect of alpha 2-agonists on gastrointestinal motility was mediated solely by the alpha 2A-subtype (63).

Part of the functional differences between alpha 2A- and alpha 2C-receptors may be explained by their distinct subcellular localization patterns (Fig. 2) (14, 47, 86, 87). In cultured sympathetic neurons from newborn mice, functional presynaptic alpha 2-receptors develop to inhibit voltage-dependent Ca2+ channels and norepinephrine release (77, 78). In sympathetic neurons, only the alpha 2A-subtype but not the alpha 2C-receptor contributed to inhibition of neurotransmitter release (81). Remarkably, inhibition of Ca2+ channels located on neuronal cell bodies and dendrites was mediated by both alpha 2A- and alpha 2C-receptors. Thus alpha 2C-receptors in neurons may require a specific itinerary to guide their expression to axonal termini.


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  		Fig. 2.   alpha 2-Adrenergic receptors differ in their trafficking itineraries in cells. When expressed in rat1 fibroblasts, alpha 2A- and alpha 2B-receptors are targeted to the plasma membrane (immunofluorescence images). On stimulation with agonist, only alpha 2B-receptors are reversibly internalized into endosomes. alpha 2C-Receptors are primarily localized in an intracellular membrane compartment, from where the alpha 2C-receptors can be translocated to the cell surface after exposure to cold temperature (29). Bottom: murine alpha 2-receptor subtypes after transient transfection into rat1 fibroblasts as described previously (14). Arrows point to alpha 2-receptors residing in the plasma membrane; arrowhead marks alpha 2C-receptors in an intracellular compartment.


    BLOOD PRESSURE REGULATION
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ABSTRACT
INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
BLOOD PRESSURE REGULATION
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alpha 2-Receptors are involved in the control of blood pressure homeostasis at a number of locations (Fig. 3). Nonselective activation of alpha 2-receptors usually leads to a biphasic blood pressure response: after a short hypertensive phase that is more pronounced after rapid intravenous injection, arterial pressure falls below the baseline. After oral application of alpha 2-agonists, the hypotensive action prevails and is being used to treat elevated blood pressure in hypertensive patients. Interestingly, the two phases of the pressure response are mediated by two different alpha 2-receptor subtypes in vivo: alpha 2B-receptors are responsible for the initial hypertensive phase, whereas the long-lasting hypotension is mediated by alpha 2A-receptors (2, 35, 38). Thus the alpha 2A-receptor is a therapeutic target for subtype-selective antihypertensive agents. The blockade of alpha 2-receptors may be of therapeutic benefit in patients with atherosclerotic coronary arteries (3), whereas it is still unknown which alpha 2-receptor subtype is responsible for the vasoconstriction in humans. An insertion/deletion polymorphism with decreased receptor desensitization of the alpha 2B-receptor subtype is associated with an increased risk for acute coronary events (69).


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  		Fig. 3.   Integrative regulation of blood pressure by different alpha 2-adrenergic receptor subtypes. Activation of alpha 2A-receptors leads to a decrease in blood pressure by inhibiting central sympathetic outflow as well as norepinephrine release from sympathetic nerves (2, 38). alpha 2B-Receptors may counteract this effect by causing direct vasoconstriction and salt-induced hypertension (22, 35). alpha 2C-Receptors participate in alpha 2-mediated vasoconstriction after exposure to cold temperature (12).

Some evidence indicates that alpha 2A-receptors also participate to a smaller degree in the vasoconstrictor action of alpha 2-agonists in mice (38). Bolus injection of norepinephrine caused transient hypertension in wild-type mice and in alpha 2B- and alpha 2C-deficient mice but not in mice lacking the alpha 2A-receptor (16). Vascular alpha 2-receptor subtypes may be differentially distributed between vascular beds. When alpha 2-agonists were injected into the carotid artery, most of the hypertensive response to alpha 2-activation was mediated by the alpha 2B-receptor (35), whereas injection into the femoral artery showed a blunted hypertensive effect in mice with the alpha 2A-D79N receptor (38). In some arteries, alpha 2-mediated vasoconstriction may even predominate over alpha 1-receptor-induced contraction, and decreased alpha -receptor responsiveness may contribute to elevated blood flood in tissue inflammation, e.g., arthritis (45).

In addition to its role as a vasoconstrictor, the alpha 2B-receptor seems to be required for the development of salt-sensitive hypertension (Fig. 3) (22, 41-43). Nephrectomy followed by Na+ loading has been established as a model of hypertension in mice (22). In this system, the development of hypertension depends on increased vasopressin release and sympathetic activation (21). Bilateral nephrectomy and saline infusion raised blood pressure in wild-type and in alpha 2A- and alpha 2C-receptor-deficient mice. However, in alpha 2B-deficient animals a small fall in arterial pressure was observed (41). Recent experiments with alpha 2B-antisense oligonucleotide injection into the lateral brain ventricle suggest that a central alpha 2B-adrenergic receptor is necessary for induction of salt-dependent hypertension (31).

Under certain conditions, even the alpha 2C-receptor subtype may contribute to vascular regulation: when kept below 37°C for a while, cutaneous arteries of the mouse tail show an alpha 2C-receptor-dependent vasoconstriction that could not be observed when the vessel segments were incubated at body temperature (12). This finding may be of great therapeutic interest for the treatment of Raynaud's disease. Patients with Raynaud's phenomenon suffer from severe periods of vasoconstriction of their fingers and toes that are usually triggered by exposure to cold. Treatment of these patients with alpha 2-adrenergic antagonists diminished the vasoconstriction (19). Interestingly, silent alpha 2C-receptors may be translocated from an intracellular receptor pool to the cell surface on cooling (Fig. 2) (29). This phenomenon has been observed in human embryonic kidney (HEK-293) cells transfected with recombinant alpha 2C-receptors: cooling of cells to 28°C evoked a redistribution of alpha 2C-receptors from the Golgi apparatus to the plasma membrane within 1 h (29). Thus inhibition of alpha 2C-receptors may prove an effective treatment for Raynaud's phenomenon.

In addition to these vascular and central neuronal mechanisms, renal alpha 2-receptors may be involved in the long-term regulation of blood pressure and fluid and electrolyte homeostasis (48, 49). Activation of renal vascular alpha 2B-receptors may lead to an increase in medullary NO production and thus counteract the vasoconstrictor effects of norepinephrine in the renal medulla (90). Via this mechanism, alpha 2B-receptors may be essential in the regulation of renal medullary blood flow and oxygen supply.


    ANALGESIA
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INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
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alpha 2-Agonists are potent analgesics, and they can potentiate the analgesic effect of opioids (75, 85, 88). Recent data indicate that all three alpha 2-receptor subtypes are involved in the regulation of pain perception in the mouse (Fig. 4).


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  		Fig. 4.   Three alpha 2-adrenergic receptor subtypes are involved in the control of pain perception in mice. A: schematic representation of alpha 2-receptor subtypes controlling spinal nociception. B: distribution of alpha 2-receptors in the mouse spinal cord by autoradiography with a non-subtype-selective alpha 2-receptor antagonist (9). In the spinal cord, the highest density of alpha 2-adrenergic receptors was observed in the superficial layers of the dorsal horns (B, arrows). Here, all 3 alpha 2-receptor subtypes control incoming nociceptive impulses: alpha 2A-receptors are required for the analgesic effect of systemically applied alpha 2-agonists, spinal alpha 2C-receptors contribute to the moxonidine-mediated analgesia, and alpha 2B-receptors are required for the spinal antinociceptive effect of nitrous oxide. See text for references. The autoradiogram shown in B was kindly provided by K. Hadamek, Würzburg, Germany.

The alpha 2A-receptor mediates the antinociception induced by systemically applied alpha 2-agonists, including clonidine and dexmedetomidine (18, 74). Compared with control mice, alpha 2-agonists were completely ineffective as an antinociceptive agent in the tail immersion or substance P test in alpha 2A-D79N mice (27). The alpha 2A-D79N mutation also blocked the synergy seen in wild-type mice between alpha 2-agonists and delta-opioid agonists (74). Interestingly, alpha 2A-receptor-deficient mice showed a reduced antinociceptive effect to isoflurane (30). However, not all alpha 2-receptor agonists required functional alpha 2A-receptors for their antinociceptive effect (Fig. 4). The imidazoline/alpha 2-receptor ligand moxonidine caused spinal antinociception that was at least partially dependent on alpha 2C-receptors (17).

Surprisingly, nitrous oxide, which is used as a potent inhalative analgesic during anesthesia, requires the alpha 2B-subtype for its antinociceptive effect (Fig. 4) (23, 60). Supraspinal opioid receptors and spinal alpha 2B-receptors are involved in the analgesic pathway for nitrous oxide. Activation of endorphin release in the periaqueductal gray by nitrous oxide stimulates a descending noradrenergic pathway that releases norepinephrine onto alpha 2B-receptors in the dorsal horn of the spinal cord (89). In mice lacking alpha 2B-receptors, the analgesic effect of nitrous oxide was completely abolished (60).


    SEDATION
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INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
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alpha 2-Agonists are used in the postoperative phase or in intensive care as sedative, hypnotic, and analgesic agents (44, 66). The sedative effects of alpha 2-agonists in mice are solely mediated by the alpha 2A-receptor subtype (32). alpha 2A-D79N mice showed no sedative response to the alpha 2-agonist dexmedetomidine (32). In contrast, mice lacking the alpha 2B- or alpha 2C-receptors did not differ in their sedative response from wild-type control mice (27, 59). Similarly, the anesthetic-sparing effect of alpha 2-agonists was completely abolished in alpha 2A-D79N mice (32).

The hypnotic effect of alpha 2-agonists is most likely mediated in the locus ceruleus. Neurons of the locus ceruleus express alpha 2A-adrenergic receptors at very high density (84). Furthermore, alpha 2A-antisense oligonucleotide injection into the locus ceruleus in rats attenuated the sedative effects of exogenous alpha 2-agonists (46).


    BEHAVIOR
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Because of their widespread distribution in the central nervous system, alpha 2-receptors affect a number of behavioral functions (5, 56, 57, 67). In particular, the alpha 2C-receptor subtype has been demonstrated to inhibit the processing of sensory information in the central nervous system of the mouse (for a recent review, see Ref. 64). Activation of alpha 2-receptors also resulted in locomotor inhibition. While direct activation of alpha 2-receptors by dexmedetomidine did not alter spontaneous motor activity in alpha 2C-receptor-deficient mice (59), D-amphetamine stimulated locomotor activity to a greater extent in alpha 2C-deficient mice than in wild-type mice (58).

Mice overexpressing alpha 2C-receptors were impaired in spatial and nonspatial water maze tests, and an alpha 2-antagonist fully reversed the water maze escape defect in these mice (4-6). The alpha 2-agonist dexmedetomidine increased swimming distance more effectively in wild-type mice than in alpha 2C-receptor-deficient mice (4). Activation of alpha 2C-receptors disrupts execution of spatial and nonspatial search patterns, whereas stimulation of alpha 2A- and/or alpha 2B-receptors may actually improve spatial working memory in mice (7). It may be concluded that novel agonists devoid of alpha 2C-receptor affinity can modulate cognition more favorably than non-subtype-selective drugs.

Altered startle reactivity and attenuation of the inhibition of the startle reflex by an acoustic prepulse have been observed in schizophrenia, and disrupted prepulse inhibition has frequently been used as an animal model for drug antipsychotic drug development. Interestingly, alpha 2C-receptor-deficient mice had enhanced startle responses, diminished prepulse inhibition, and shortened attack latency in the isolation-aggression test (57). Thus drugs acting via the alpha 2C-receptor may have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, posttraumatic stress disorder, and drug withdrawal. In addition to the alpha 2C-subtype, the alpha 2A-receptor has an important role in modulating behavioral functions. Experiments using gene-targeted mice indicate that the alpha 2A-receptor may play a protective role in some forms of depression and anxiety, and this receptor may mediate part of the antidepressant effects of imipramine (67). Thus alpha 2A- and alpha 2C-receptors complement each other to integrate central nervous system function and behavior.


    OTHER PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICAL TARGETS
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alpha 2-Receptors are involved in the regulation of body temperature as well as seizure threshold. Activation of central alpha 2A-receptors causes a powerful antiepileptogenic effect in mice (28). Two receptor subtypes, alpha 2A and alpha 2C, may be involved in the hypothermic action of alpha 2-agonists (27, 59). Another important function of alpha 2-agonists is their inhibitory effect on intraocular pressure. The alpha 2-agonists apraclonidine and brimonidine are currently being used to lower intraocular pressure in patients with glaucoma (52, 68). In adipose tissue, alpha 2-receptors inhibit lipolysis (72, 73) and alpha 2-receptors are potential targets for the treatment of obesity. Mice expressing human alpha 2-receptors in fat tissue in vivo, in the absence of beta 3-adrenergic receptors, developed high-fat diet-induced obesity (83). However, the precise role of individual alpha 2-receptor subtypes in the control of lipolysis is unknown at present.


    CONCLUSIONS
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Genetic deletion of alpha 2-adrenergic receptor subtype genes in mice has greatly enhanced our understanding of the physiological functions and therapeutic potential of individual alpha 2-receptor subtypes. alpha 2-Adrenergic receptors are important regulators of sympathetic tone, neurotransmitter release, blood pressure, and intraocular pressure. alpha 2-Receptor activation causes sedation and potent analgesia. Further potential therapeutic functions may be unraveled with the help of mouse models with deleted alpha 2-receptor genes. Before these genetic animal models were available, it was hypothesized that each biological function of alpha 2-receptors would be mediated by one receptor subtype. Thus it was reasonable to assume that novel subtype-specific pharmacological agonists or antagonists would be of great therapeutic value because of their reduced potential for alpha 2-receptor-mediated side effects. However, with more and more studies of the alpha 2-receptor physiology in gene-targeted mice being published, the situation became more complicated than initially anticipated. Indeed, only a few biological functions of alpha 2-receptors were found to be mediated by one single alpha 2-adrenergic receptor subtype. Examples are the hypotension or sedation caused by alpha 2A-receptor activation.

For other alpha 2-receptor-mediated functions, two different strategies seem to have emerged to regulate adrenergic signal transduction: some biological functions are controlled by two counteracting alpha 2-receptor subtypes, e.g., alpha 2A-receptors decrease sympathetic outflow and blood pressure, whereas the alpha 2B-subtype increases blood pressure by direct vasoconstriction. In contrast, the inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves requires two receptor subtypes, alpha 2A and alpha 2C, with similar but complementary effects. Similarly, pain perception is controlled at several levels of by one of the three alpha 2-receptor subtypes.

The fact that more than one receptor subtype may be involved in regulating one particular physiological function does not limit the therapeutic potential of novel subtype-selective drugs for alpha 2-adrenergic receptors. However, it emphasizes that knowledge of the spectrum of in vivo biological effects is mandatory before making precise predictions about the in vivo effects of subtype-specific drugs. For treatment of hypertension, a selective alpha 2A-receptor agonist without affinity for the alpha 2B-receptor might be advantageous. As alpha 2B-receptors counteract the hypotensive effect of alpha 2A-receptor activation, a selective alpha 2A-agonist could be given at a lower dose to achieve similar blood pressure lowering with reduced sedative side effects. In addition, a combination of agonistic and antagonistic properties may become desirable, for instance, for antihypertensives, e.g., alpha 2A-agonist and alpha 2B-antagonist. The primary target for alpha 2-mediated pain modulation would be the alpha 2B-receptor. As illustrated by the potent analgesic effect of nitrous oxide, alpha 2B-receptor activation might be a very promising analgesic strategy. Whether alpha 2C-receptors are equally effective in inhibiting pain pathways in the spinal cord has to be tested in future studies (17). The main advantage of alpha 2B- or alpha 2C-receptor-specific agonists for antinociception would be their lack of sedative side effects compared with nonselective alpha 2-agonists that also stimulate alpha 2A-receptors. In addition, they would not cause respiratory depression and addiction, which are two major problems associated with opioid therapy. In anesthesia and intensive care, the availability of pairs of subtype-selective agonists and antagonists might be of great benefit (66). alpha 2A-Receptor-mediated sedation that can be rapidly reversed by a selective alpha 2-antagonist may be used in future human anesthesia (as it is already being used with non-subtype-selective agonists/antagonists in veterinary anesthesia). Finally, mice lacking all alpha 2-receptor subtypes will also be essential tools to determine the function of imidazoline receptors and the potential of future imidazoline receptor drugs (24, 51).

Further investigation of the specific function of alpha 2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.


    ACKNOWLEDGEMENTS

Our work has been supported by the Deutsche Forschungsgemeinschaft.


    FOOTNOTES

Address for reprint requests and other correspondence: L. Hein, Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany (hein{at}toxi.uni-wuerzburg.de).

10.1152/ajpregu.00123.2002


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
alpha 2-ADRENERGIC RECEPTOR GENES
GENE-TARGETED MICE LACKING...
WHICH alpha 2-RECEPTOR SUBTYPE IS...
BLOOD PRESSURE REGULATION
ANALGESIA
SEDATION
BEHAVIOR
OTHER PHYSIOLOGICAL FUNCTIONS...
CONCLUSIONS
REFERENCES

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