Calcitonin gene‐related peptide regulates gene transcription in primary afferent neurons

• Published in: Journal of neurochemistry 2004-12, Vol.91 (6), p.1417-1429
• Main Authors: Anderson, L. E., Seybold, V. S.
• Format: Article
• Language: English
• Subjects: Aging - metabolism; Animals; Animals, Newborn; Biochemistry and metabolism; Biological and medical sciences; Calcitonin Gene-Related Peptide - pharmacology; calcitonin gene‐related peptide; Calcium - metabolism; Cells, Cultured; Central nervous system; Cyclic AMP - biosynthesis; Cyclic AMP - physiology; cyclic AMP response element binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - physiology; dorsal root ganglion; Fundamental and applied biological sciences. Psychology; Ganglia, Spinal - cytology; Gene Expression Regulation - drug effects; Intracellular Membranes - metabolism; Mitogen-Activated Protein Kinases - physiology; mitogen‐activated protein kinase/extracellular receptor kinase kinase; Neurons, Afferent - metabolism; Osmolar Concentration; Phosphorylation - drug effects; protein kinase A; Rats; Rats, Sprague-Dawley; Response Elements - physiology; Signal Transduction - physiology; Transcription, Genetic - drug effects; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02833.x

Although primary afferent neurons express receptors for calcitonin gene‐related peptide (CGRP), understanding of the cellular effects of these receptors is limited. We determined that CGRP receptors regulate gene transcription in primary afferent neurons through a cyclic AMP (cAMP)‐dependent pathway. CGRP increased cAMP in neonatal dorsal root ganglion (DRG) neurons in a concentration‐dependent manner that was blocked by the receptor antagonist CGRP8‐37. The response to CGRP also occurred in adult DRG cells. In contrast, CGRP did not alter the concentration of free intracellular calcium in neonatal or adult DRG neurons. Immunohistochemical data showed that one downstream effect of the cAMP signaling pathway was phosphorylation of cAMP response element binding (CREB) protein, suggesting that CGRP regulates gene expression. This interpretation was supported by evidence that CGRP increased CRE‐dependent gene transcription in neurons transiently transfected with a CRE‐luciferase DNA reporter construct. The effect of CGRP on gene transcription was inhibited by H89, myristoylated‐protein kinase A inhibitor14−22‐amide and U0126, indicating that protein kinase A and mitogen‐activated protein kinase/extracellular receptor kinase kinase are enzymes that mediate effects of CGRP on gene transcription. Therefore, CGRP receptors may regulate expression of proteins by primary afferent neurons during development and in response to tissue‐damaging stimuli.