Cyclic AMP-dependent protein kinase A and protein kinase C phosphorylate α4β2 nicotinic receptor subunits at distinct stages of receptor formation and maturation
Open accessAbstract
Neuronal nicotinic receptor alpha4 subunits associated with nicotinic alpha4beta2 receptors are phosphorylated by cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC), but the stages of receptor formation during which phosphorylation occurs and the functional consequences of kinase activation are unknown. SH-EP1 cells transfected with DNAs coding for human alpha4 and/or beta2 subunits were incubated with (32)Pi, and PKA or PKC was activated by forskolin or phorbol 12,13-dibutyrate, respectively. Immunoprecipitation and immunoblotting of proteins from cells expressing alpha4beta2 receptors or only alpha4 subunits were used to identify free alpha4 subunits, and alpha4 subunits present in immature alpha4beta2 complexes and mature alpha4beta2 pentamers containing complex carbohydrates. In the absence of kinase activation, phosphorylation of alpha4 subunits associated with mature pentamers was three times higher than subunits associated with immature complexes. PKA and PKC activation increased phosphorylation of free alpha4 subunits on different serine residues; only PKC activation phosphorylated subunits associated with mature alpha4beta2 receptors. Activation of both PKA and PKC increased the density of membrane-associated receptors, but only PKC activation increased peak membrane currents. PKA and PKC activation also phosphorylated beta2 subunits associated with mature alpha4beta2 receptors. Results indicate that activation of PKA and PKC leads to the phosphorylation alpha4beta2 receptors at different stages of receptor formation and maturation and has differential effects on the expression and function of human alpha4beta2 receptors.
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SePhaChARNS does not explicitly depend on direct phosphorylation or other covalent modification of the nAChR.
“First, SePhaChARNS does not explicitly depend on direct phosphorylation (86) or other covalent modification of the nAChR.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [86]
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- Authors
- Pollock, V. V., Pastoor, T., Katnik, C., Cuevas, J., & Wecker, L.
- Affiliations
- University of South Florida (US)
- ORCID
- Cuevas, J.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 158
- Issue
- 4
- Pages
- 1311-1325
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC2664513
- OpenAlex
- W2072803594
- Cited by
- 31
- References
- 42
- Citations by year
- 2025: 1 · 2023: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2015: 6 · 2014: 5 · 2013: 2 · 2012: 1
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (DA14010, R01DA014010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- α4β2 nicotinic acetylcholine receptor, protein kinase A, protein kinase C, receptor phosphorylation, receptor maturation, alpha4 subunit, beta2 subunit, serine phosphorylation, forskolin, phorbol 12,13-dibutyrate, membrane currents
- MeSH terms
- Acetylcholine, Analysis of Variance, Antibodies, Autoradiography, Cell Line, Transformed, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Colforsin, Humans, Indoles, Membrane Potentials, Models, Biological, Phosphorylation, Protein Kinase C, Receptors, Nicotinic, Serine, Time Factors, Transfection, Electrophoresis, Gel, Two-Dimensional, Phorbol 12,13-Dibutyrate, Cyclic AMP-Dependent Protein Kinases, Patch-Clamp Techniques, Biotinylation, Protein Interaction Mapping, Immunoprecipitation
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