Transporters

Alexander, SPH; Mathie, A; Peters, JA

doi:10.1111/j.1476-5381.2011.01649_8.x

Cited by 4 publications

(5 citation statements)

References 506 publications

(206 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To assess the tonic cardiorespiratory effects of basal nTS EAAT2, rats were subjected to bilateral injections of increasing doses of the EAAT2‐selective (Alexander et al . ) antagonist dihydrokainate (DHK, 0.5–5 m m ; ≤90 nl). Similar volumes of artificial cerebrospinal fluid (aCSF) served as vehicle controls.…”

Section: Methodsmentioning

confidence: 99%

“…Initial baseline depressor, SSNA and PhrNA responses to unilateral nTS microinjections of glutamate (3-5 mM, 30 nl) were determined, to functionally identify the cardiorespiratory nTS (Foley et al 1998;Clark et al 2011;. To assess the tonic cardiorespiratory effects of basal nTS EAAT2, rats were subjected to bilateral injections of increasing doses of the EAAT2-selective (Alexander et al 2011) antagonist dihydrokainate (DHK, 0.5-5 mM; ࣘ90 nl). Similar volumes of artificial cerebrospinal fluid (aCSF) served as vehicle controls.…”

Section: Ethical Approval and Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes

Matott

Kline

Hasser

2017

The Journal of Physiology

View full text Add to dashboard Cite

Glutamatergic signalling is critical in the nucleus tractus solitarii (nTS) for cardiorespiratory homeostasis and initiation of sensory reflexes, including the chemoreflex activated during hypoxia. Maintenance of nTS glutamate concentration occurs in part through astrocytic excitatory amino acid transporters (EAATs). We previously established the importance of EAATs in the nTS by demonstrating their inhibition produced neuronal excitation to alter basal cardiorespiratory function. Since EAAT2 is the most expressed EAAT in the nTS, this study specifically determined EAAT2's role in nTS astrocytes, its influence on neuronal and synaptic properties, and ultimately on basal and reflex cardiorespiratory function. The EAAT2-specific antagonist dihydrokainate (DHK) was microinjected into the anaesthetized rat nTS or applied to rat nTS slices. DHK produced depressor, bradycardic and sympathoinhibitory responses and reduced neural respiration in the intact rat, mimicking responses to glutamate excitation. DHK also enhanced responses to glutamate microinjection. DHK elevated extracellular nTS glutamate concentration, depolarized neurons and enhanced spontaneous EPSCs. EAAT2 block also augmented action potential discharge in chemosensitive nTS neurons. Glial recordings confirmed EAAT2 is functional on nTS astrocytes. Neuronal excitation and cardiorespiratory effects following EAAT2 inhibition were due to activation of putative extrasynaptic AMPA receptors as their antagonism blocked DHK responses in the intact rat nTS and the slice. The DHK-induced elevation of extracellular glutamate and neuronal excitation augmented chemoreflex-mediated pressor, sympathoexcitatory and minute neural ventilation responses in the rat. These data shed new light on the important role astrocytic EAAT2 plays on buffering nTS excitation and overall cardiorespiratory function.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Ethical Approval and Animalsmentioning

confidence: 99%

Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes

Matott

Kline

Hasser

2017

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Reversing eNOS uncoupling represents a therapeutic option to treat CVD (Forstermann and Li, 2011; Zhang et al, 2011). While most interventions are experimentally restricted, eNOS cofactor BH 4 potentially leads to eNOS recoupling in the human vasculature (Forstermann and Li, 2011; Zhang et al, 2011).…”

Section: Drugs That Affect No Generation/turnover: a Treatment For Agmentioning

confidence: 99%

“…While most interventions are experimentally restricted, eNOS cofactor BH 4 potentially leads to eNOS recoupling in the human vasculature (Forstermann and Li, 2011; Zhang et al, 2011). Infusion of BH 4 has been shown to recover eNOS bioactivity in hypercholesterolemic patients, hypertensive subjects, and smokers (revised by Forstermann and Li, 2011; Zhang et al, 2011). Importantly, improved endothelium-dependent vasodilation associated to BH 4 infusion was significantly more pronounced in elderly than in young subjects (Higashi et al, 2006).…”

Section: Drugs That Affect No Generation/turnover: a Treatment For Agmentioning

confidence: 99%

Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities

Cau¹,

Carneiro²,

Tostes³

2012

Front. Physio.

View full text Add to dashboard Cite

Vascular aging is the term that describes the structural and functional disturbances of the vasculature with advancing aging. The molecular mechanisms of aging-associated endothelial dysfunction are complex, but reduced nitric oxide (NO) bioavailability and altered vascular expression and activity of NO synthase (NOS) enzymes have been implicated as major players. Impaired vascular relaxation in aging has been attributed to reduced endothelial NOS (eNOS)-derived NO, while increased inducible NOS (iNOS) expression seems to account for nitrosative stress and disrupted vascular homeostasis. Although eNOS is considered the main source of NO in the vascular endothelium, neuronal NOS (nNOS) also contributes to endothelial cells-derived NO, a mechanism that is reduced in aging. Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases. Accordingly, this review will focus on drugs that modulate NO bioavailability, such as nitrite anions and NO-releasing non-steroidal anti-inflammatory drugs, hormones (dehydroepiandrosterone and estrogen), statins, resveratrol, and folic acid, since they may be useful to treat/to prevent aging-associated vascular dysfunction. The impact of these therapies on life quality in elderly and longevity will be discussed.

show abstract

“…Moreover, these events were shown to be associated with G protein signaling- or growth factor-mediated pathways which were not blocked by tamoxifen antagonist, leading to the prediction that an alternative membrane-bound estrogen receptor exists (Wehling, 1997; Hammes and Levin, 2007; Meyer and Barton, 2009). In fact, an orphan GPCR was identified as an estrogen-binding membrane GPCR from vascular and cancer cells and is now included in the official GPCR nomenclature and was designated GPER or GPR30 by the International Union of Pharmacology (Revankar et al, 2005; Thomas et al, 2005; Prossnitz et al, 2008a; Alexander et al, 2011). Its localization seems to be predominantly intracellular due to the constitutive internalization of plasma membrane GPER (Figure 3) (Revankar et al, 2005; Otto et al, 2008; Cheng et al, 2011; Sanden et al, 2011).…”

Section: The Estrogen Receptors Er/gpermentioning

confidence: 99%

Acting on Hormone Receptors with Minimal Side Effect on Cell Proliferation: A Timely Challenge Illustrated with GLP-1R and GPER

Gigoux¹,

Fourmy²

2013

Front. Endocrinol.

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) constitute a large family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. GPCR are involved in a wide variety of physiological processes, including in the neuroendocrine system. GPCR are also involved in many diseases and are the target of 30% of marketed medicinal drugs. Whereas the majority of the GPCR-targeting drugs have proved their therapeutic benefit, some of them were associated with undesired effects. We develop two examples of used drugs whose therapeutic benefits are tarnished by carcinogenesis risks. The chronic administration of glucagon-like peptide-1 (GLP-1) analogs widely used to treat type-2 diabetes was associated with an increased risk of pancreatic or thyroid cancers. The long-term treatment with the estrogen antagonist tamoxifen, developed to target breast cancer overexpressing estrogen receptors ER, presents agonist activity on the G protein-coupled estrogen receptor which is associated with an increased incidence of endometrial cancer and breast cancer resistance to hormonotherapy. We point out and discuss the need of pharmacological studies to understand and overcome the undesired effects associated with the chronic administration of GPCR ligands. In fact, biological effects triggered by GPCR often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling networks are engaged following GPCR activation appears to be primordial to unveil their contribution in the physiological and physiopathological processes. The development of biased agonists to elucidate the role of the different signaling mechanisms mediated by GPCR activation will allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1R biased ligands promoting insulin secretion without inducing pro-tumoral effects would offer therapeutic benefit.

show abstract

Transporters

Cited by 4 publications

References 506 publications

Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes

Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes

Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities

Acting on Hormone Receptors with Minimal Side Effect on Cell Proliferation: A Timely Challenge Illustrated with GLP-1R and GPER

Contact Info

Product

Resources

About