In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

MacMillan, Leigh B.; Lakhlani, Parul P.; Hein, Lutz; Piascik, Michael T.; Guo, Tian-Zhi; Lovinger, David M.; Maze, Mervyn; Limbird, Lee E.

doi:10.1016/s1054-3589(08)60796-6

Cited by 17 publications

(9 citation statements)

References 9 publications

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“…Recent work with relatively selective agonists and antagonists, radiolabels, and specific molecular probes in several species, including genetically engineered mice, have begun to elucidate specific functions for the various ␣ 2 AR subtypes (26). The latter studies have been particularly useful in identifying subtype-specific functions.…”

Section: Resultsmentioning

confidence: 99%

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

Small¹,

Forbes²,

Brown³

et al. 2000

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

Small¹,

Forbes²,

Brown³

et al. 2000

Journal of Biological Chemistry

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“…Unlike the ␣ 2C -adrenoreceptor, both the ␣ 2A -and ␣ 2B -adrenergic receptors target efficiently to the plasma and lack an intracellular ER distribution (1, 2, 6). The ␣ 2A -adrenoreceptors are found in many tissues including platelets where they modulate platelet aggregation and in the central nervous system where they influence pain perception and blood pressure (18,19). The ␣ 2B -adenoceptors subtype is found in vascular smooth muscle where their activation leads to elevation of systemic blood pressure (20).…”

Section: Discussionmentioning

confidence: 99%

Cell-type Specific Targeting of the α2c-Adrenoceptor

Hurt¹,

Feng

Kobilka

2000

Journal of Biological Chemistry

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G protein-coupled receptors mediate transmission of information across the plasma membrane by activation of membrane-associated G-proteins that couple to intracellular effector systems. Although most G protein-coupled receptor ligands are confined to the extracellular space, for some G proteincoupled receptors, such as the thrombin receptor, thyrotropinreleasing hormone receptor, and the ␣ 2C -adrenoreceptor, a significant proportion of the receptor population is found in intracellular compartments. In the case of thrombin receptors, evidence suggests that the intracellular pool of receptors may serve as a reservoir, capable of restoring functional, noncleaved thrombin receptors to the plasma membrane after the cell has been exposed to thrombin (3). A minor fraction of thyrotropin-releasing hormone receptors expressed in HEK cells are targeted to the plasma membrane while a larger fraction is found in an intracellular compartment and are nonfunctional (4). However, when the thyrotropin releasing hormone receptors were expressed in two pituitary cell lines (GH3 and GHY cells) the receptors were found predominantly in the plasma membrane and to be functional by binding assays.For the ␣ 2C -adrenoreceptor, the functional status and role of an intracellular pool is less clear. This is particularly interesting in light of ␣ 2C

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“…Surprisingly, the density of ␣ 2A -D79N receptors in the mouse brain was decreased to ϳ20% of the normal level (38). Thus, in most (but not all) functional tests, the ␣ 2A -D79N receptor had characteristics resembling a functional "knockout" of the ␣ 2A -receptor (40). One important exception was the observation that the presynaptic inhibitory function of the ␣ 2A -D79N receptor was normal or only slightly blunted in intact tissues (2).…”

Section: ␣2-receptor Subtypesmentioning

confidence: 98%

Physiological significance of α₂-adrenergic receptor subtype diversity: one receptor is not enough

Philipp

Brede

Hein

2002

American Journal of Physiology-Regulatory, Integrative and Comp

290

214

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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.

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In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

Cited by 17 publications

References 9 publications

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

Cell-type Specific Targeting of the α2c-Adrenoceptor

Physiological significance of α₂-adrenergic receptor subtype diversity: one receptor is not enough

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In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

Cited by 17 publications

References 9 publications

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling

Cell-type Specific Targeting of the α2c-Adrenoceptor

Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough

Contact Info

Product

Resources

About

Physiological significance of α₂-adrenergic receptor subtype diversity: one receptor is not enough