Genetic Variations of α2-Adrenergic Receptors Illuminate the Diversity of Receptor Functions

Cottingham, Christopher; Chen, Yunjia; Peng, Yin; Wang, Qin

doi:10.1016/b978-0-12-384921-2.00008-2

Cited by 9 publications

(9 citation statements)

References 146 publications

(165 reference statements)

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“…Our previous study [5] postulated a model whereby DMI exerts its therapeutic antidepressant effects through a downregulation of central nervous system α 2A AR expression, correcting the pathobiological increases in α 2A AR density and activity associated with clinical depression (reviewed in [25]). The present data demonstrate that DMI in a physiologically relevant ratio with NE can effectively turn on MAPK signaling at that is lacking in response to the physiological level (e.g.…”

Section: Resultsmentioning

confidence: 99%

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

Cottingham

Jones

Wang

2012

Biochemical and Biophysical Research Communications

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The precise physiological effects of antidepressant drugs, and in particular their actions at non-monoamine transporter targets, are largely unknown. We have recently identified the tricyclic antidepressant drug desipramine (DMI) as a direct ligand at the α2A adrenergic receptor (AR) without itself driving heterotrimeric G protein/downstream effector activation (Cottingham et al, J. Biol. Chem. 286: 36063–75). In this study, we report our novel finding that DMI modulates α2AAR signaling in response to the endogenous agonist norepinephrine (NE). DMI acted as a signaling potentiator, selectively enhancing NE-induced α2AAR-mediated ERK1/2 MAPK signaling. This potentiation of ERK1/2 activation was observed as an increase in NE response sensitivity and a prolongation of the activation kinetics. DMI in a physiologically relevant ratio with NE effectively turned on ERK1/2 signaling that is lacking in response to physiological NE alone. Further, the DMI-induced ERK1/2 potentiation relied on heterotrimeric Gi/o proteins and was arrestin-independent. This modulatory effect of DMI on NE signaling provides novel insight into the effects of this antidepressant drug on the noradrenergic system which it regulates, insight which enhances our understanding of the therapeutic mechanism for DMI.

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Section: Resultsmentioning

confidence: 99%

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

Cottingham

Jones

Wang

2012

Biochemical and Biophysical Research Communications

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“…Blockade of α 2A AR activity would reduce the detrimental effects of NE on AD-related pathology through this receptor subtype and would further boost NE, given that the α 2A AR is also an autoreceptor, to improve cognition. Increased α 2A AR density and/or activity have been associated with type 2 diabetes mellitus and depression (30,31), both of which are risk factors for AD.…”

Section: Discussionmentioning

confidence: 99%

α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

Chen

Peng

Che

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of amyloid β (Aβ) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aβ generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α 2A adrenergic receptor (α 2A AR). Genetic deficiency of the α 2A AR significantly reduces, whereas stimulation of this receptor enhances, Aβ generation and AD-related pathology. Activation of α 2A AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α 2A AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by β secretase. The α 2A AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α 2A AR-promoted Aβ generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α 2A AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α 2A AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α 2 AR antagonists would be an effective therapeutic strategy for AD.adrenergic receptor | amyloid | processing | SorLA | sorting E xcess amyloid β (Aβ) peptides in the brain are a neuropathological hallmark of Alzheimer's disease (AD) and are generally accepted as the key pathogenic factor of the disease (1). Aβ is generated by two sequential cleavages of amyloid precursor protein (APP) by β and γ secretase, whereas cleavage by α secretase within the Aβ domain precludes Aβ generation (2, 3). APP and the secretases undergo endocytic sorting into various organelles, such as the trans-Golgi network, the plasma membrane, and endosomes (2-6). The initial step of APP processing by α versus β secretase preferentially occurs in distinct compartments of the cell. Although α secretase-mediated cleavage of APP occurs on the plasma membrane, β secretase primarily interacts with and cleaves APP in endosomes (2-6). Therefore, endocytic sorting of APP into different membranous compartments, causing it to coreside or avoid a particular secretase, plays a decisive role in APP proteolytic processing. Consistent with this notion, abnormalities of the endocytic pathway have been found to precede Aβ deposition in late-onset AD (7).Retrograde sorting of APP from endosomes to trans-Golgi network mediated by the vacuolar protein sorting-10 (Vps10) family proteins and the retromer complex represents a critical mechanism to prevent amyloidogenic processing of APP (8-10) and has recently emerged as a potential targe...

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“…There are three α 2 AR subtypes, the α 2A , α 2B , and α 2C , which are encoded by separate genes (Bylund et al, 1994; Cottingham et al, 2011a; Wang, 2011). Among these, the α 2A AR is the predominantly expressed subtype within the central nervous system (De Vos et al, 1992; Sastre and Garcia-Sevilla, 1994; Wang et al, 1996), and is primarily responsible for the central noradrenergic functions described above (Altman et al, 1999; Franowicz et al, 2002; MacMillan et al, 1996; Stone et al, 1997).…”

Section: The α2 Adrenergic Receptor Familymentioning

confidence: 99%

“…We have recently reviewed genetic evidence for α 2 AR involvement in depressive disorders (Cottingham et al, 2011a), and so here we will simply emphasize a few of the most intriguing of these studies. The first comes from Sequeira and colleagues, who uncovered a possible link between the N251K variant of the α 2A AR and suicide, with the mutant allele found only in the suicide group and not in matched controls (Sequeira et al, 2004).…”

Section: Dysregulation Of α2 Adrenergic Receptor Density and Activmentioning

confidence: 99%

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

Cottingham

Wang

2012

Neuroscience & Biobehavioral Reviews

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Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the α2ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of α2ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α2AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state α2ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α2AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α2AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key α2AR accessory proteins in depressive disorders and discuss their potential contribution to α2AR dysfunction.

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Genetic Variations of α2-Adrenergic Receptors Illuminate the Diversity of Receptor Functions

Cited by 9 publications

References 146 publications

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

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Genetic Variations of α2-Adrenergic Receptors Illuminate the Diversity of Receptor Functions

Cited by 9 publications

References 146 publications

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

Desipramine selectively potentiates norepinephrine-elicited ERK1/2 activation through the α2A adrenergic receptor

α 2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

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α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction