Localization and function of NK(3) subtype tachykinin receptors of layer V pyramidal neurons of the guinea-pig medial prefrontal cortex.
Animals; Autoradiography/methods; Dose-Response Relationship; Drug; Drug Interactions; Excitatory Amino Acid Antagonists/pharmacology; Excitatory Postsynaptic Potentials/drug effects/radiation effects; Guinea Pigs; In Vitro Techniques; Iodine Isotopes/pharmacokinetics; Male; Membrane Potentials/drug effects/physiology/radiation effects; Neurokinin B/analogs & derivatives/pharmacokinetics; Neurokinin-3/agonists/antagonists & inhibitors/*metabolism; Patch-Clamp Techniques; Peptide Fragments/pharmacology; Prefrontal Cortex/*cytology; Protein Binding/drug effects; Pyramidal Cells/drug effects/*metabolism; Quinolines/pharmacology; Quinoxalines/pharmacology; Receptors; Substance P/analogs & derivatives/pharmacology; Valine/analogs & derivatives/pharmacology
The NK(3) subtype of tachykinin receptor has been implicated as a modulator of synaptic transmission in several brain regions, including the cerebral cortex. The localization and expression of NK(3) receptors within the brain vary from species to species. In addition, the pharmacology of NK(3) receptor-specific antagonists shows significant species variability. Among commonly used animal models, the pharmacology of the guinea-pig NK(3) receptor most closely resembles that of the human NK(3) receptor. Here, we provide anatomical localization studies, receptor binding studies, and studies of the electrophysiological effects of NK(3) receptor ligands of guinea-pig cortex using two commercially available ligands, the NK(3) receptor peptide analog agonist senktide, and the quinolinecarboxamide NK(3) receptor antagonist SB-222,200. Saturation binding studies with membranes isolated from guinea-pig cerebral cortex showed saturable binding consistent with a single high affinity site. Autoradiographic studies revealed dense specific binding in layers II/III and layer V of the cerebral cortex. For electrophysiological studies, brain slices were prepared from prefrontal cortex of 3- to 14-day-old guinea pigs. Whole cell recordings were made from layer V pyramidal neurons. In current clamp mode with a K(+)-containing pipette solution, senktide depolarized the pyramidal neurons and led to repetitive firing of action potentials. In voltage clamp mode with a Cs(+)-containing pipette solution, senktide application produced an inward current and a concentration-dependent enhancement of the amplitude and the frequency of spontaneous excitatory postsynaptic potentials. The glutamatergic nature of these events was demonstrated by block by glutamate receptor antagonists. The effects of senktide were blocked by SB-222,200, an NK(3) receptor antagonist. Taken together, these results are consistent with a functional role for NK(3) receptors located on neurons in the cerebral cortex. In layer V pyramidal neurons of the medial prefrontal cortex, activation of the NK(3) receptor system plays an excitatory role in modulating synaptic transmission.
Simmons M A; Sobotka-Briner C D; Medd A M
Neuroscience
2008
2008-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuroscience.2008.08.037" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2008.08.037</a>
Par-4 induces cholinergic hypoactivity by suppressing ChAT protein synthesis and inhibiting NGF-inducibility of ChAT activity.
*Intracellular Signaling Peptides and Proteins; Amyloid beta-Peptides/pharmacology; Animals; Apoptosis Regulatory Proteins; Carrier Proteins/genetics/*physiology; Choline O-Acetyltransferase/*antagonists & inhibitors/biosynthesis/metabolism; Enzyme Induction/drug effects; Gene Expression/physiology; Leucine Zippers/genetics; Nerve Growth Factor/*pharmacology; Osmolar Concentration; PC12 Cells; Peptide Fragments/pharmacology; Rats
Profound reductions in choline acetyl-transferase (ChAT) activity are reliable markers for cholinergic hypoactivity associated with cognitive function deficit in Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a novel mediator of neuronal apoptosis associated with the pathogenesis of AD. Par-4 contains a leucine zipper domain (Leu.zip) that presumably mediates protein-protein interactions critical for its functions in apoptosis. Par-4 activity can be effectively blocked by overexpression of Leu. zip because it exerts a dominant negative action possibly by competitively blocking the interaction of Par-4 with other proteins. Whether Par-4 participates in regulation of cholinergic signaling has not been determined. We report that overexpression of Par-4 results in apoptotic and non-apoptotic reductions in ChAT activity in transfected PC12 cells following exposure to a toxic concentration (50 microM) of aggregated amyloid beta peptide 1-42 (Abeta 1-42) and a non-toxic concentration (1 microM) of soluble Abeta 1-42, respectively. Non-apoptotic reduction in ChAT activity induced by Par-4 can be completely blocked by co-overexpression of Leu.zip, indicating that enhanced Par-4 activity is a necessary event for cholinergic hypoactivity in PC12 cells. Further studies found that Par-4 induces non-apoptotic reduction in ChAT activity by: (1) reducing ChAT protein levels following exposure to non-toxic concentration of Abeta, and (2) blocking the cellular capability to increase ChAT activity following exposure to nerve growth factor (NGF). The role of Par-4 in inducing cholinergic hypoactivity may have significant implications in the understanding and the treatment of memory impairment in AD.
Guo Q; Xie J; Du H
Brain research
2000
2000-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(00)02559-2" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(00)02559-2</a>