N-Methyl-d-aspartate Receptor Mechanosensitivity Is Governed by C Terminus of NR2B Subunit

Singh, Pallab; Doshi, Shachee; Spaethling, Jennifer M.; Hockenberry, Adam J.; Patel, Tapan P.; Geddes-Klein, Donna M.; Lynch, David R.; Meaney, David F.

doi:10.1074/jbc.m111.253740

Cited by 62 publications

(56 citation statements)

References 73 publications

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“…Motivated by the early work using physical models and finite element simulations, several investigators developed microscope-based systems to study directly the relationship between the mechanical deformation and resultant biochemical signaling [183][184][185][186][187][188][189]. As a result, we now know that both neural and glial cells respond to mechanical deformation, that synaptically localized receptors are uniquely mechanosensitive, show immediate alterations in their physiological properties, and changes occur across both excitatory and inhibitory neurons [190][191][192][193][194][195]. At higher loading conditions, an additional mechanism of injury appears, which is the nonspecific, transient opening of pores within the membrane [183,186,[196][197][198][199][200][201][202] after cellular deformation.…”

Section: Linking the Physical Response To The Biological Responsementioning

confidence: 99%

The Mechanics of Traumatic Brain Injury: A Review of What We Know and What We Need to Know for Reducing Its Societal Burden

Meaney

Morrison

Bass

2014

Journal of Biomechanical Engineering

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126

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Traumatic brain injury (TBI) is a significant public health problem, on pace to become the third leading cause of death worldwide by 2020. Moreover, emerging evidence linking repeated mild traumatic brain injury to long-term neurodegenerative disorders points out that TBI can be both an acute disorder and a chronic disease. We are at an important transition point in our understanding of TBI, as past work has generated significant advances in better protecting us against some forms of moderate and severe TBI. However, we still lack a clear understanding of how to study milder forms of injury, such as concussion, or new forms of TBI that can occur from primary blast loading. In this review, we highlight the major advances made in understanding the biomechanical basis of TBI. We point out opportunities to generate significant new advances in our understanding of TBI biomechanics, especially as it appears across the molecular, cellular, and whole organ scale.

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Section: Linking the Physical Response To The Biological Responsementioning

confidence: 99%

The Mechanics of Traumatic Brain Injury: A Review of What We Know and What We Need to Know for Reducing Its Societal Burden

Meaney

Morrison

Bass

2014

Journal of Biomechanical Engineering

Self Cite

200

126

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“…Activation of PKC can lead to a wide range of alterations within the NMDAR: 1) potentiation or desensitization, 47 2) Mg + block sensitivity, 48 and 3) receptor trafficking. 49 An electrophysiological study demonstrated a potentiation of NMDAR currents due to the activation of PKC by 4β-phorbol-12-myristate-13-acetate (4β-PMA).…”

Section: Nmdar Signalingmentioning

confidence: 99%

“…47 With regards to Mg 2+ block sensitivity, PKC is essential for phosphorylation at mechanosensitive domains of the NR1/NR2B subunits restoring mechanical stretch of the NMDAR following a potential Mg 2+ block. 48,51 Furthermore, PKC mediates the phosphorylation (activation) of nitric oxide synthase (NOS) leading to the generation of nitric oxide (NO). 52 Consistent with this view is the finding that inhibition of PKC by chelerythrine attenuated glutamate-induced increases in NO in cerebellar granule cells.…”

Section: Nmdar Signalingmentioning

confidence: 99%

N-Methyl-D-Aspartate Receptor Signaling and Function in Cardiovascular Tissues

McGee

Abdel‐Rahman

2016

Journal of Cardiovascular Pharmacology

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Excellent reviews on central N-methyl-D-Aspartate receptor (NMDAR) signaling and function in cardiovascular regulating neuronal pools have been reported. However, much less attention has been given to NMDAR function in peripheral tissues, particularly the heart and vasculature, although a very recent review discusses such function in the kidney. In this short review, we discuss the NMDAR expression and complexity of its function in cardiovascular tissues. In conscious (contrary to anesthetized) rats, activation of the peripheral NMDAR triggers cardiovascular oxidative stress via the PI3K-ERK1/2-NO signaling pathway, which ultimately leads to elevation in blood pressure. Evidence also implicates Ca2+ release, in the peripheral NMDAR-mediated pressor response. Despite evidence of circulating potent ligands (e.g. D- and L-aspartate, L-homocysteic acid and quinolonic acid) as well as their co-agonist (e.g. glycine or D-serine), the physiological role of peripheral cardiovascular NMDAR remains elusive. Nonetheless, the cardiovascular relevance of the peripheral NMDAR might become apparent when its signaling is altered by drugs, like alcohol, which interact with the NMDAR or its downstream signaling mechanisms.

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“…Moreover, the agonist affinity of the NMDAR is altered after mechanical stretch. The molecular tethering of the receptor to the cytoskeleton is key for this mechanosensing property, and there is a potentially intriguing control of this mechanosensitivity within a single serine residue of the NR2B subunit of the receptor (Singh et al, 2012). Controlling mechanosensitivity through the NR2B subunit is potentially significant because of the association between NR1/NR2B receptor subtypes and neuronal demise after mechanical injury (DeRidder et al, 2006).…”

Section: Are There Important Mechanosensors?mentioning

confidence: 99%