Calcitonin gene-related peptide (CGRP) increases in sensory neurons after
inflammation and plays an important role in abnormal
pain responses, but how this
neuropeptide is regulated is not well understood. Both
activin A and
nerve growth factor (
NGF) increase in skin after
inflammation and induce CGRP in neurons in vivo and in vitro. This study was designed to understand how neurons integrate these two signals to regulate the
neuropeptide important for inflammatory
pain. In adult dorsal root ganglion neurons,
NGF but not
activin alone produced a dose-dependent increase in CGRP
mRNA. When added together with
NGF,
activin synergistically increased CGRP
mRNA, indicating that sensory neurons combine these signals. Studies were then designed to learn if that combination occurred at a common receptor or shared intracellular signals. Studies with
activin IB receptor or
tyrosine receptor kinase A inhibitors suggested that each
ligand required its cognate receptor to stimulate the
neuropeptide. Further,
activin did not augment
NGF-initiated intracellular
mitogen-activated protein kinase signals but instead stimulated Smad phosphorylation, suggesting these
ligands initiated parallel signals in the cytoplasm.
Activin synergy required several
NGF intracellular signals to be present. Because
activin did not further stimulate, but did require
NGF intracellular signals, it appears that
activin and
NGF converge not in receptor or cytoplasmic signals, but in transcriptional mechanisms to regulate CGRP in rat sensory neurons after
inflammation.