Adrenoceptors and signal transduction in neurons

Hein, Lutz

doi:10.1007/s00441-006-0285-2

Cited by 198 publications

(174 citation statements)

References 91 publications

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“…Whereas application of NE has been shown to generate membrane hyperpolarization in a proportion (ϳ54%) of principal neurons in layer II of the EC (28) via ␣ 2 AR-mediated activation of K ϩ channels (27), which may partially explain its inhibitory effects on glutamatergic transmission, the following questions still remain unaddressed. First, what subtype(s) of ␣ 2 ARs is/are involved in NE-mediated hyperpolarization in the EC, because members of the ␣ 2 AR family include the ␣ 2A , ␣ 2B , and ␣ 2C subtypes (31)? Second, does NE have any effects on the excitability of neurons in other layers of the EC, because the superficial layers are the sender and the deep layers are the recipient of hippocampal information?…”

Section: The Entorhinal Cortex (Ec)mentioning

confidence: 99%

“…␣ 2 AR subtypes are classified as ␣ 2A , ␣ 2B , and ␣ 2C (31). We next identified the roles of these three subtypes of ␣ 2 ARs in NE-induced hyperpolarization by combining pharmacological approaches and knock-out (KO) animal models.…”

Section: Ne Inhibits the Neuronal Excitability In The Superficial Laymentioning

confidence: 99%

“…Requires PKA Activity-␣ 2A ARs are coupled to G␣ i proteins resulting in inhibition of cAMP production and PKA activity (31). We next examined the roles of this intracellular pathway in NE-induced inhibition of neuronal excitability in the EC.…”

Section: Ne-induced Hyperpolarization Is Dependent On G␣ I Proteins Andmentioning

confidence: 99%

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Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels

Xiao

Deng

Rojanathammanee

et al. 2009

Journal of Biological Chemistry

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The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by ␣ 2A adrenergic receptors and required the functions of G␣ i proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K ؉ channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels. The entorhinal cortex (EC)2 is an essential structure in the limbic system that is closely related to emotional control (1), consolidation and recall of memories (2, 3), Alzheimer disease (4, 5), schizophrenia (6, 7), and temporal lobe epilepsy (8, 9). The physiological and pathological roles of the EC are likely to be determined by its unique position in the brain; the EC serves as the interface to control the flow of information into and out of the hippocampus. Afferents from the olfactory structures, parasubiculum, perirhinal cortex, claustrum, amygdala, and neurons in the deep layers of the EC (layers V-VI) (10, 11) converge onto the superficial layers (layer II/III) of the EC, whereas the axons of principal neurons in layer II form the major component of perforant path that innervates the dentate gyrus and CA3 (12), and those of the pyramidal neurons in layer III form the temporoammonic pathway and synapse onto the distal dendrites of pyramidal neurons in the CA1 and subiculum (12)(13)(14). The output from the hippocampus is then projected to the deep layers of the EC that relay information back to the superficial layers (15-18) and to other cortical areas (10).The EC receives abundant noradrenergic projections from the locus coeruleus in the brain stem (19 -21) and expresses ␣ 1 (22), ␣ 2 (23-25), and ␤ (26) adrenergic receptors (ARs), although the identities of cells expressing these ARs in the EC remain to be determined. Accordingly, application of norepinephrine (NE) in the EC has been shown to inhibit glu...

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Section: The Entorhinal Cortex (Ec)mentioning

confidence: 99%

Section: Ne Inhibits the Neuronal Excitability In The Superficial Laymentioning

confidence: 99%

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Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels

Xiao

Deng

Rojanathammanee

et al. 2009

Journal of Biological Chemistry

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“…Both facilitatory and inhibitory effects on Gal mRNA expression in SCG neurons by administration of alpha 2-adrenoreceptor ligands implicated that Gal mRNA expression was closely related to the activity of alpha 2-adrenoreceptors. Alpha 1-adrenoreceptors are coupled to G q /11-mediated pathways, which increase intracellular inositol-trisphosphate (IP 3 ) and Ca 2+ concentrations (Hein, 2006). And also, the alpha 1-adrenoreceptor agonist phenylephrine was found to elicit a concentration-dependent increase in NE release from rat sympathetic neurons (Boehm and Huck, 1997).…”

Section: Discussionmentioning

confidence: 98%

“…Activation of the inhibitory Gα i protein by alpha 2-adrenoreceptors leads to the inhibition of adenylyl cyclase, thus resulting in decreased cellular cAMP levels (Hein, 2006). Alpha 2-adrenoceptors inhibited either electrically or K + -evoked NE release from sympathetic neurons (Boehm and Huck, 1997).…”

Section: Discussionmentioning

confidence: 99%

Effects of Alpha 1- and Alpha 2-Adrenoreceptor Stimulation on Galanin mRNA Expression in Primary Cultured Superior Cervical Ganglion Neurons

Xing¹,

Chen²,

Liu³

et al. 2011

Biomolecules and Therapeutics

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Abstractan inhibitory modulator of cholinergic and noradrenergic neurotransmission (Miller et al., 1999;Van Hoomissen et al., 2004;Landry et al., 2005;Hobson et al., 2006). Gal is co-localized with norepinephrine (NE) in several regions of the brain, such as locus coeruleus, bed nucleus of the stria terminalis, amygdala, cortex and hippocampus (Hokfelt et al., 1998;Kozicz, 2001;Xu et al., 2001;Holmes et al., 2002;Barrera et al., 2006;Ogren et al., 2006;Simpson et al., 2006). Gal hyperpolarizes noradrenergic locus coeruleus neurons at high concentrations (10 -6 -10 -7 mol/L) and enhances NE-induced hyperpolarization at low concentrations (10 -9 mol/L) (Hokfelt et al., 1998). It has been shown that Gal expression was regulated by NE in the magnocellular neurons of supraoptic nucleus in an ex vivo acute model of rat hypothalamic slices (Melnikova et al., 2006) and in cultured dorsal root ganglion (DRG) neuronsOriginal Article

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New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

David

Malhotra

2022

Ann Clin Transl Neurol

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There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

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Adrenoceptors and signal transduction in neurons

Cited by 198 publications

References 91 publications

Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels

Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels

Effects of Alpha 1- and Alpha 2-Adrenoreceptor Stimulation on Galanin mRNA Expression in Primary Cultured Superior Cervical Ganglion Neurons

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

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