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The Journal of Neuroscience, March 1, 2003, 23(5):1816

Calcitonin Gene-Related Peptide Regulates Expression of Neurokinin₁ Receptors by Rat Spinal Neurons

Virginia S. Seybold¹, Kenneth E. McCarson², Paul G. Mermelstein¹, Rachel D. Groth¹, and Lia G. Abrahams¹

¹ Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and ² Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160

Although neurokinin 1 (NK1) receptors contribute to hyperalgesia, and their expression is increased in the spinal cord during peripheral inflammation, little is known regarding the signaling molecules and the second messenger pathways that they activate in regulating the expression of the NK1 receptor gene. Because the promoter region of the NK1 receptor contains a cAMP response element (CRE), we tested the hypothesis that calcitonin gene-related peptide (CGRP) regulates the expression of NK1 receptors via a pathway involving activation of the transcription factor cAMP response element binding protein (CREB). Experiments were conducted on primary cultures of neonatal rat spinal neurons. Treatment of cultures with CGRP for 8-24 hr increased ¹²⁵I-substance P binding on spinal neurons; the increase in binding was preceded by an elevation in NK1 receptor mRNA. The CGRP-induced change in ¹²⁵I-substance P binding was concentration-dependent and was inhibited by the antagonist CGRP_8-37. CGRP increased phosphorylated CREB immunoreactivity and CRE-dependent transcription in neurons, indicating the involvement of the transcription factor CREB. Evidence that CGRP increased cAMP levels in spinal neurons and that the protein kinase A inhibitor H89 attenuated CGRP-induced CRE-dependent transcription suggests that the intracellular pathway stimulated by CGRP leads to activation of protein kinase A. Collectively these data define a role for CGRP as a signaling molecule that induces expression of NK1 receptors in spinal neurons. The data provide evidence that a neuropeptide receptor controls gene expression in the CNS and add another dimension to understanding the cotransmission of substance P and CGRP by primary afferent neurons.

Key words: CGRP; spinal cord; neurokinin receptor; CREB; substance P; prostaglandin E2

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351816-09$05.00/0

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