<i>In Vitro</i> Phosphorylation of Rat Brain Nicotinic Acetylcholine Receptor by cAMP‐Dependent Protein Kinase

Nakayama, Hitoshi; Okuda, Hiromichi; Nakashima, T.

doi:10.1111/j.1749-6632.1993.tb38092.x

Cited by 9 publications

(10 citation statements)

References 4 publications

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“…The major consensus phosphorylation sequences on nAChR subunits lie within the large intracellular loop between TM domains 3 and 4 (Swope et al, 1992). Several of these sites have been shown to be directly phosphorylated in vitro by PKA or PKC (Vijayaraghavan et al, 1990;Nakayama et al, 1993;Moss et al, 1996;Wecker et al, 2001), and may underlie the observed phosphorylation of certain nAChRs in vivo (Viseshakul et al, 1998). In particular, serine 368 on the ␣4 subunit, may underlie the enhanced recovery from desensitization of oocyteexpressed ␣4␤2 nAChRs mediated by Ca 2ϩ /PKC, because mutation of this residue limits recovery (Fenster et al, 1999a) and, although it has a higher affinity for PKA, serine 368 is a substrate for PKC (Wecker et al, 2001).…”

Section: Regulation Of Desensitizationmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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Section: Regulation Of Desensitizationmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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“…Several in vitro studies have demonstrated that some of these sites are directly phosphorylated by PKA or PKC (Vijayaraghavan et al 1990;Nakayama et al 1993;Moss et al 1996;Wecker et al 2001). Biochemical studies on rat α4β2-nAChR either isolated from rat brain (Nakayama et al 1993) or immunoprecipitated from Xenopus oocytes (Hsu et al 1997) provided evidence that the α4 subunit is a substrate for phosphorylation by PKA.…”

Section: Protein Kinase Modulation Of Nachr Desensitization-phosphorymentioning

confidence: 99%

“…Biochemical studies on rat α4β2-nAChR either isolated from rat brain (Nakayama et al 1993) or immunoprecipitated from Xenopus oocytes (Hsu et al 1997) provided evidence that the α4 subunit is a substrate for phosphorylation by PKA.…”

Section: Protein Kinase Modulation Of Nachr Desensitization-phosphorymentioning

confidence: 99%

Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking

Ochoa

Lasalde‐Dominicci

2007

Cell Mol Neurobiol

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Patients with schizophrenia present with deficits in specific areas of cognition. These are quantifiable by neuropsychological testing and can be clinically observable as negative signs. Concomitantly, they self-administer nicotine in the form of cigarette smoking. Nicotine dependence is more prevalent in this patient population when compared to other psychiatric conditions or to non-mentally ill people. The target for nicotine is the neuronal nicotinic acetylcholine receptor (nAChR). There is ample evidence that these receptors are involved in normal cognitive operations within the brain. This review describes neuronal nAChR structure and function, focusing on both cholinergic agonist-induced nAChR desensitization and nAChR upregulation. The several mechanisms proposed for the nAChR up-regulation are examined in detail. Desensitization and up-regulation of nAChRs may be relevant to the physiopathology of schizophrenia. The participation of several subtypes of neuronal nAChRs in the cognitive processing of non-mentally ill persons and schizophrenic patients is reviewed. The role of smoking is then examined as a possible cognitive remediator in this psychiatric condition. Finally, pharmacological strategies focused on neuronal nAChRs are discussed as possible therapeutic avenues that may ameliorate the cognitive deficits of schizophrenia.

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“…During the past decade, studies have suggested that the expression and function of a4b2 receptors are regulated post-translationally by phosphorylation/dephosphorylation mechanisms (Rothhut et al 1996;Eilers et al 1997;Gopalakrishnan et al 1997;Fenster et al 1999;Jeanclos et al 2001;Nashmi et al 2003). Initial studies demon-strated that rat a4b2 receptors, either isolated from brain (Nakayama et al 1993) or expressed in and immunoprecipitated from Xenopus oocytes (Hsu et al 1997;Wecker et al 2001), were phosphorylated in vitro by cAMPdependent protein kinase (PKA). Further in vivo studies using rat a4b2 receptors expressed in Xenopus oocytes (Viseshakul et al 1998) or human a4b2 receptors stably expressed in SH-EP1 cells (Pacheco et al 2003) indicated that when cells were incubated with 32 Pi, radioactivity was incorporated by a4 subunits, and that phosphorylation increased following activation of either PKA or protein kinase C (PKC).…”

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confidence: 99%

Cyclic AMP‐dependent protein kinase (PKA) phosphorylates Ser362 and 467 and protein kinase C phosphorylates Ser550 within the M3/M4 cytoplasmic domain of human nicotinic receptor α4 subunits

Pollock

Pastoor

Wecker

2007

Journal of Neurochemistry

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Studies have suggested that the expression, translocation, and function of a4b2 nicotinic receptors may be modulated by a4 subunit phosphorylation, but little direct evidence exists to support this idea. The objective of these experiments was to identify specific serine/threonine residues on a4 subunits that are phosphorylated in vivo by cAMP-dependent protein kinase and protein kinase C (PKC). To accomplish this, DNAs coding for human a4 subunits containing alanines in place of serines/threonines predicted to represent phosphorylation sites were constructed, and transiently transfected with the DNA coding for wild-type b2 subunits into SH-EP1 cells. Cells were pre-incubated with 32 Pi and incubated in the absence or presence of forskolin or phorbol 12,13-dibutyrate. Immunoprecipitated a4 subunits were subjected to immunoblot, autoradiographic and phosphoamino acid analyses, and two-dimensional phosphopeptide mapping. Results confirmed the presence of two a4 protein bands, a major band of 71/75 kDa and a minor band of 80/ 85 kDa. Phosphoamino acid analysis of the major band indicated that only serine residues were phosphorylated. Phosphopeptide maps demonstrated that Ser362 and 467 on the M3/M4 cytoplasmic domain of the a4 subunit represent major cAMP-dependent protein kinase phosphorylation sites, while Ser550 also contained within this major intracellular loop is a major site for protein kinase C phosphorylation.

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In Vitro Phosphorylation of Rat Brain Nicotinic Acetylcholine Receptor by cAMP‐Dependent Protein Kinase

Cited by 9 publications

References 4 publications

Desensitization of neuronal nicotinic receptors

Desensitization of neuronal nicotinic receptors

Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking

Cyclic AMP‐dependent protein kinase (PKA) phosphorylates Ser362 and 467 and protein kinase C phosphorylates Ser550 within the M3/M4 cytoplasmic domain of human nicotinic receptor α4 subunits

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