Activation of the mitogen-activated protein kinase (MAPK) cascade recently was discovered to play an important role in synaptic plasticity in area CA1 of rat hippocampus. However, the upstream mechanisms regulating MAPK activity and the downstream effectors of MAPK in the hippocampus are uncharacterized. In the present studies we observed that hippocampal MAPK activation is regulated by both the PKA and PKC systems; moreover, we found that a wide variety of neuromodulatory neurotransmitter receptors (metabotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, and beta-adrenergic receptors) couple to MAPK activation via these two cascades. In additional studies we observed that PKC is a powerful regulator of CREB phosphorylation in area CA1. MAPK plays a critical role in transcriptional regulation by PKC, because MAPK activation is a necessary component for increased CREB phosphorylation in response to the activation of this kinase. Surprisingly, we also observed that MAPK activation is necessary for PKA coupling to CREB phosphorylation in area CA1. Overall, these studies indicate an unexpected richness of diversity in the regulation of MAPK in the hippocampus and suggest the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plasticity.

https://www.jneurosci.org/content/jneuro/19/11/4337.full.pdf

The Mitogen-Activated Protein Kinase Cascade Couples PKA and PKC to cAMP Response Element Binding Protein Phosphorylation in Area CA1 of Hippocampus

The α7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is abundantly expressed in hippocampus and is implicated in modulating neurotransmitter release and in binding α-bungarotoxin (α-BGT). A null mutation for the α7 subunit was prepared by deleting the last three exons of the gene. Mice homozygous for the null mutation lack detectable mRNA, but the mice are viable and anatomically normal. Neuropathological examination of the brain revealed normal structure and cell layering, including normal cortical barrel fields; histochemical assessment of the hippocampus was also normal. Autoradiography with [3H]nicotine revealed no detectable abnormalities of high-affinity nicotine binding sites, but there was an absence of high-affinity [125I]α-BGT sites. Null mice also lack rapidly desensitizing, methyllycaconitine-sensitive, nicotinic currents that are present in hippocampal neurons. The results of this study indicate that the α-BGT binding sites are equivalent to the α7-containing nAChRs that mediate fast, desensitizing nicotinic currents in the hippocampus. These mice demonstrate that the α7 subunit is not essential for normal development or for apparently normal neurological function, but the mice may prove to have subtle phenotypic abnormalities and will be valuable in defining the functional role of this gene product in vivo.

https://www.jneurosci.org/content/jneuro/17/23/9165.full.pdf

Mice Deficient in the α7 Neuronal Nicotinic Acetylcholine Receptor Lack α-Bungarotoxin Binding Sites and Hippocampal Fast Nicotinic Currents

Intracellular accumulation of β-amyloid1–42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer’s disease

Diversity of vertebrate nicotinic acetylcholine receptors

Exogenous application of acetylcholine elicits inward currents in hippocampal interneurons that are mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors, but synaptic responses mediated via such receptors have never been reported in mammalian brain. In the present study, EPSCs were evoked in hippocampal interneurons in rat brain slices by electrical stimulation and were recorded by using whole-cell voltage-clamp techniques. Nicotinic EPSCs were isolated pharmacologically, using antagonists to block other known types of ligand-gated ion channels, and then were tested with either alpha-bungarotoxin or methyllycaconitine, which are selective antagonists for nicotinic acetylcholine receptors that contain the alpha7 receptor subunit. Each antagonist proved highly effective at reducing the remaining synaptic current. Evoked alpha7-mediated nicotinic EPSCs also were desensitized by superfusion with 1 microM nicotine, had extrapolated reversal potentials near 0 mV, and showed strong inward rectification at positive potentials. In several interneurons, methyllycaconitine-sensitive spontaneous EPSCs also were observed that exhibited a biphasic decay rate very similar to that of the alpha7-mediated evoked response. These studies provide the first demonstration of a functional cholinergic synapse in the mammalian brain, in which the primary postsynaptic receptors are alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors.

https://www.jneurosci.org/content/jneuro/18/20/8228.full.pdf

Synaptic Potentials Mediated via α-Bungarotoxin-Sensitive Nicotinic Acetylcholine Receptors in Rat Hippocampal Interneurons

The α-Bungarotoxin-binding Nicotinic Acetylcholine Receptor from Rat Brain Contains Only the α7 Subunit

The alpha7 subunit of the neuronal nicotinic acetylcholine receptor, when expressed in Xenopus oocytes, forms homooligomeric ligand-gated ion channels that are blocked by a snake toxin, alpha-bungarotoxin. The amino-terminal extracellular domain of the alpha7 sequence has three consensus sites for asparagine-linked glycosylation (N46DS, N90MS, and N133AS). In this study, we show that alpha7 expressed either in vivo or in vitro is a glycoprotein of 57 kDa. In addition, we demonstrate by site-directed mutagenesis that all three consensus sites are used for glycosylation. To elucidate the role(s) of asparagine-linked glycosylation in the formation and function of the alpha7 receptor, wild-type and glycosylation-deficient alpha7 subunits were expressed in COS cells and oocytes. We examined biochemical and physiological properties of expressed receptors and found that alpha7 glycosylation mutations do not affect homooligomerization and surface protein expression of the alpha7 receptor but do affect surface expression of alpha-bungarotoxin binding sites and the function of the receptor. Our data indicate that asparagine-linked glycosylation is required for the expression of a functional alpha7 receptor in oocytes.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.1998.70010349.x

Contributions of N-Linked Glycosylation to the Expression of a Functional α7-Nicotinic Receptor in Xenopus Oocytes

The neuronal nicotinic acetylcholine receptor (nAChR) subunit α7 forms a principal neuronal α-bungarotoxin binding site that is thought to have a neuromodulatory and developmental role. Here we present evidence that the expression of α7 homo-oligomeric receptors in Xenopus oocytes is dependent on the activity of the peptidyl prolyl isomerase (PPIase) cyclophilin. We show further that the expression of the hetero-oligomeric muscle nAChR is devoid of such a requirement, and that the muscle receptor non-alpha subunits relieve the α7 receptor from this requirement. We conclude that cyclophilin might be uniquely required as a PPIase or a molecular chaperone in the folding and assembly of α7 homo-oligomers.

A Cyclophilin-Dependent Mechanism for α7 Neuronal Nicotinic Acetylcholine Receptor Maturation

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The α-Bungarotoxin-binding Nicotinic Acetylcholine Receptor from Rat Brain Contains Only the α7 Subunit

Contributions of N-Linked Glycosylation to the Expression of a Functional α7-Nicotinic Receptor in Xenopus Oocytes

A Cyclophilin-Dependent Mechanism for α7 Neuronal Nicotinic Acetylcholine Receptor Maturation