Identification of a Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in non-N-methyl-D-aspartate glutamate receptors.

Yakel, Jerrel L.; Vissavajjhala, Prabhakar; Derkach, V. A.; Brickey, Debra A.; Soderling, Thomas R.

doi:10.1073/pnas.92.5.1376

Cited by 90 publications

(53 citation statements)

References 57 publications

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“…Inconsistent with the conclusion from these topology studies, however, were findings from several groups that residues in the M3-M4 linker of non-NMDA glutamate receptors could be phosphorylated (21)(22)(23)(24)(25). Most notably, two separate laboratories had determined that a serine residue (Ser-684) in the M3-M4 linker of GluR6 acted as a substrate for protein kinase A (PKA) (21,22).…”

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confidence: 63%

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

Wood¹,

VanDongen

1997

Journal of Biological Chemistry

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While attempting to map a central region in the M3-M4 linker of the N-methyl-D-aspartate receptor NR1 subunit, we found that mutation of a single position, Ala-714, greatly reduced the apparent affinity for glycine. Proximal N-glycosylation localized this region to the extracellular space. Glycine affinities of additional Ala-714 mutations correlated with side chain volume. Substitution of alanine 714 with cysteine did not alter glycine sensitivity, although this mutant was rapidly inhibited by dithionitrobenzoate. Glycine protected the A714C mutant from modification by dithionitrobenzoate, whereas the co-agonist L-glutamate was ineffective. These experiments place Ala-714 in the glycine binding pocket of the N-methyl-D-aspartate receptor, a determination not predicted by previous structural models based on bacterial periplasmic binding protein homology.The N-methyl-D-aspartate (NMDA) 1 receptor is distinguished among the ionotropic glutamate receptors by several properties. The receptor possesses a unique Ca 2ϩ permeability and a voltage-dependent Mg 2ϩ block (1). These two features define the NMDA receptor's role in several important physiologic phenomena, including long term potentiation, neuronal development, and excitotoxicity (2). However, the functional characteristic that may most differentiate the NMDA receptor from other glutamate receptors is a requirement for the coagonist glycine (3, 4). Occupancy of both glutamate and glycine binding sites is necessary for receptor activation, and the two sites are allosterically coupled (5, 6). The distinct glycine binding site has been suggested to play a role in regulation of NMDA receptor desensitization (7). While several residues in the amino terminus of NR1 have been demonstrated to greatly influence glycine affinity, binding is also modulated by the contributing NR2 subunits (8). Indeed, the glycine binding site is a current experimental target for therapeutic intervention in the hours immediately following ischemic stroke (9).Despite functional differences among the glutamate receptors, several recent studies have converged upon a single topology model for the ionotropic glutamate receptor family (10 -14). Speculation of alternate glutamate receptor topology was suggested by several early investigations (15)(16)(17)(18)(19). Several subsequent systematic studies concluded that non-NMDA glutamate receptor subunits possessed a three-transmembrane domain architecture (11,12,20). By generating functional N-linked glycosylation mutants of the NMDA NR1 subunit, we tested the hypothesized existence of a conserved hairpin pore structure similar to that found in voltage-gated K ϩ channels (13), thus supporting the three-transmembrane domain model. An important consequence of the new three-transmembrane domain configuration is an extracellular location of the M3-M4 linker.Inconsistent with the conclusion from these topology studies, however, were findings from several groups that residues in the M3-M4 linker of non-NMDA glutamate receptors could be phosphorylated (2...

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confidence: 63%

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

Wood¹,

VanDongen

1997

Journal of Biological Chemistry

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“…(iv) One of the targets for CaM-K II is the AMPA receptor itself. Thus, activated CaM-K II can phosphorylate AMPA receptors in the postsynaptic density and can enhance responses to AMPA receptor agonists in cultured hippocampal neurons (15) and acutely isolated dorsal root ganglion neurons (27 evoked by activating GluRl receptors expressed in oocytes are also enhanced by CaM-K II (28).…”

Section: Resultsmentioning

confidence: 99%

Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.

Lledo

Hjelmstad

Mukherji

et al. 1995

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

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412

227

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“…Kinases involved in receptor phosphorylation are cAMP-dependent protein kinase, protein kinase C, and CaM kinase. CaM kinase II phosphorylation was shown to involve regulation of NMDA, GABAA, and human~.t-opioid receptor activity (McDonald and Moss, 1994;Mestek et al, 1995;Yakel et al, 1995).…”

Section: Resultsmentioning

confidence: 99%

Site Mutation in the Rat μ‐Opioid Receptor Demonstrates the Involvement of Calcium/Calmodulin‐Dependent Protein Kinase II in Agonist‐Mediated Desensitization

Koch

Kroslak

Mayer

et al. 1997

Journal of Neurochemistry

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The rat 1z-opioid receptor (rMOR1), expressed in human embryonic kidney 293 (HEK293) cells, showsa desensitization to the inhibitory effect of the js agonist DAMGO on adenylate cyclase activity within 4 h of DAMGO preincubation. To investigate the role of calcium/calmodulin-dependent protein kinase Il (CaM kinase Il) on 1s-opioid receptor desensitization, we coexpressed rMOR1 and constitutively active CaM kinase Il in HEK293 cells. This coexpression led to a faster time course of agonist-induced desensitization of the~-opioid receptor. The increase ofdesensitization could not be observed with a te-opioid receptor mutant (S261A!S266A) that lacks two putative CaM kinase Il phosphorylation sites in the third intracellular loop. In addition, injection of CaM kinase Il in Xenopus oocytes led only to desensitization of expressed rMOR1, but not of an S261 A! S266A receptor mutant. These results suggest that phosphorylation of Ser 251 and Ser266 by CaM kinase II is involved in the desensitization of the 1s-opioid receptor. Key Words:~t-Opioid receptor -Desensitization -Calcium! calmodulin -dependent protein kinase phosphorylation-G protein-activated channelXenopus oocytes. J. Neurochem. 69, 1767-1770 (1997).Extensive physiological, behavioral, and pharmacological studies have defined three major types of opioid receptors, designated~.t, 6, and K (Wood and Iyengar, 1988;Corbett et al., 1993). The activation of all three opioid receptor types can inhibit adenylate cyclase. In addition, opiates have been shown to open K~channels and to close Ca 2~channels (North, 1993).In Xenopus oocytes expressing opioid receptors and the G protein-gated, inwardly rectifying K channel (known as KGA or GIRK1), application of the~.t agonist [D-Ala2, MePhe4,G1y5-ol] enkephalin (DAMGO) evoked a dose-dependent increase in K + conductance (Chen and Yu, 1994). Chen and Yu (1994) demonstrated that repeated agonist stimulation of the~i-opioid receptor coexpressed with GIRK 1 in Xenopus oocytes resulted in desensitization of the u-activated current response. Using the Xenopus expression system, it has also been reported that phosphorylation by protein kinase C and Ca2~/calmodulin-dependentprotein kinase II (CaM kinase II) modulates desensitization of the human p~-opioidreceptor (Mestek et al., 1995), whereas receptor desensitization of the 6-opioidreceptor is influenced by protein kinase C (Ueda et al., 1994(Ueda et al., , 1995. Due to the experimental conditions, it is not clearly shown in these experiments whether the target of these kinases is the opioid receptor, the G protein, the K + channel, or some intermediary factors. Moreover, Kovoor et al. (1995) suggested that the desensitization of the rat~t-opioid receptor in the Xenopus oocyte system is receptor-independent and caused by an inactivation of the K + channel itself.To investigate further the role of CaM kinase II in opioid receptor desensitization, we used, in addition to the Xenopus oocyte expression system, the human embryonic kidney 293 (HEK293) cell line for expressing the ...

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Identification of a Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in non-N-methyl-D-aspartate glutamate receptors.

Cited by 90 publications

References 57 publications

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.

Site Mutation in the Rat μ‐Opioid Receptor Demonstrates the Involvement of Calcium/Calmodulin‐Dependent Protein Kinase II in Agonist‐Mediated Desensitization

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