Regulation of sensory neuron precursor proliferation by cyclic GMP-dependent protein kinase.
Cyclic GMP (cGMP) is a molecular messenger involved in diverse cellular processes. Recently, cGMP-dependent protein kinase (cGK) type II was determined to be a regulator of endochondral ossification and bone growth, identifying a role for cGMP in the regulation of cellular proliferation. Here, we demonstrate the presence of cGK type I (cGKI) in cells of the developing trigeminal ganglia. cGKI occurs in some proliferating precursors as evidenced by double labeling with an antibody to cGKI and 5-bromo-2'-deoxyuridine(BrdU) incorporation. Inhibition of cGKI with KT5823 or Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) in chick embryos results in a 30-40% decrease in trigeminal ganglia cell number, and this effect is independent of nitric oxide synthase (NOS). In addition, inhibition of cGKI with Rp-8-pCPT-cGMPS results in a 60% decrease in BrdU incorporation in the trigeminal ganglia of embryonic day 5 chicks. We find that PC12 cells expressing cGKI proliferate more rapidly and incorporate more BrdU than do control cells. The cGKI inhibitor Rp-8-pCPT-cGMPS decreases proliferation and BrdU incorporation in transfected PC12 cells but has no effect on control cells. The PC12 cells do not express NOS, indicating that this effect is also independent of NOS. Thus, cGKI regulates the proliferation of sensory neurons as a result of activation of a NOS-independent pathway, representing a novel pathway by which the number of sensory neurons is regulated.
Firestein
B L
BL
Department of Physiology, School of Medicine, University of California at San Francisco, 94143-0444, USA.
Bredt
D S
DS
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D002642:Chick Embryo / Q000166:cytology / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009475:Neurons, Afferent / Q000166:cytology*; D016716:PC12 Cells / Q000473:pathology; D051381:Rats; D013234:Stem Cells / Q000166:cytology*; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D012668:Trigeminal Ganglion / Q000196:embryology / Q000378:metabolism
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D004791:Enzyme Inhibitors; D013873:Thionucleotides; D017869:Cyclic GMP-Dependent Protein Kinases; D001973:Bromodeoxyuridine; D006152:Cyclic GMP