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New Targets for GPCRs Coupled to cAMP and Protein Kinase A
a Mental Retardation Research Center, Semel Institute for Neuroscience, Jonsson Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, California 90095, USA b Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA c INSERM U732, Hopital St Antoine, 75012 Paris, France d INSERM U676, Hôpital Robert Debré, 75019 Paris, France
Key Words: hedgehog • cancer • seven transmembrane • vasoactive intestinal peptide (VIP)
Address for correspondence: James A. Waschek, NRB 345, UCLA, 635 Charles E. Young Dr. South, Los Angeles, CA 90095-7332. Voice: 310-825-0179; fax: 310-206-5061. e-mail: jwaschek{at}mednet.ucla.edu
Hedgehog (HH) is a secreted protein named for the bristle phenotype observed in Drosophila embryos that lack the corresponding gene. Three homologs have been characterized in vertebrates, all which have critical roles in the development of multiple organ systems. Moreover, these proteins regulate stem cell production and activation during tissue repair after injury, and appear to drive proliferation in a variety of type of tumors, including those arising in the brain, foregut, lung, breast, pancreas, stomach, and prostate. Early evidence from Drosophila, and later work in vertebrates established the cAMP/protein kinase A (PKA) pathway as a major pathway which opposes HH signaling, doing so by phosphorylating intracellular signaling mediators and targeting them for degradation. Thus, it seems possible that ligands which activate G protein–coupled receptors (GPCR) may act in some cases to oppose or enhance HH signaling. We studied a possible interaction of pituitary adenylyl cyclase-activating peptide (PACAP) with sonic hedgehog (SHH) in the developing cerebellum, where both PACAP and SHH are know to act. PACAP and the PAC1-specific agonist, maxadilan, were found to completely block the proliferative action of SHH on developing cerebellar granule neurons. It remains to be determined if HH/GPCR antagonistic interactions play additional important roles in development, plasticity, tissue repair, cancer, and other processes.
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