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NEUROPHARMACOLOGY

Inhibition of Native and Recombinant Nicotinic Acetylcholine Receptors by the Myristoylated Alanine-Rich C Kinase Substrate Peptide

Laboratories of Neurobiology (E.A.G., R.C.K., M.A.M., J.L.Y.) and Signal Transduction (P.J.B.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina

A variety of peptide ligands are known to inhibit the function of neuronal nicotinic acetylcholine receptors (nAChRs), including small toxins and brain-derived peptides such as β-amyloid_1–42 and synthetic apolipoproteinE peptides. The myristoylated alanine-rich C kinase substrate (MARCKS) protein is a major substrate of protein kinase C and is highly expressed in the developing and adult brain. The ability of a 25-amino acid synthetic MARCKS peptide, derived from the effector domain (ED), to modulate nAChR activity was tested. To determine the effects of the MARCKS ED peptide on nAChR function, receptors were expressed in Xenopus laevis oocytes, and two-electrode voltage-clamp experiments were performed. The MARCKS ED peptide completely inhibited acetylcholine (ACh)-evoked responses from 7 nAChRs in a dose-dependent manner, yielding an IC₅₀ value of 16 nM. Inhibition of ACh-induced responses was both activity- and voltage-independent. The MARCKS ED peptide was unable to block -bungarotoxin binding. A MARCKS ED peptide in which four serine residues were replaced with aspartate residues was unable to inhibit 7 nAChR-mediated currents. The MARCKS ED peptide inhibited ACh-induced 4β2 and 2β2 responses, although with decreased potency. The effects of the MARCKS ED peptide on native nAChRs were tested using acutely isolated rat hippocampal slices. In hippocampal interneurons, the MARCKS ED peptide was able to block native 7 nAChRs in a dose-dependent manner. The MARCKS ED peptide represents a novel antagonist of neuronal nAChRs that has considerable utility as a research tool.

Address correspondence to: Jerrel L. Yakel, National Institute of Environmental Health Sciences, F2-08, P.O. Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709. E-mail: yakel{at}niehs.nih.gov