Regulation of Sensory Neuron Precursor Proliferation by Cyclic GMP‐Dependent Protein Kinase

Abstract

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.

Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I

“…PKG-I additionally regulates the proliferation of sensory neurons during embryogenesis (27), and its deficiency caused axon guidance defects of nociceptive neurons within the developing dorsal root entry zone (2). The present results show that, in terms of formalin-induced nociception, PKG-I inhibition is as effective as PKG-I deficiency.…”

Activation of the PI3-K/Akt Pathway Mediates cGMP Enhanced-Neurogenesis in the Adult Progenitor Cells Derived from the Subventricular Zone

“…Here, we show that nestin-positive neural progenitor cells and neurons express PDE5, which may account for the observation that Sildenafil selectively increased numbers of TuJ-1-positive cells. Cyclic GMP-dependent protein kinases contribute to the effects of cGMP on cellular and physiologic function (Firestein et al, 1998). Our data show that the PDE5 inhibitor, Sildenafil, significantly increased expression of type II PKG, suggesting that type II PKG may be involved in cGMP-enhanced neurogenesis.…”

cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age

“…24,25 These results also indicate that patients with taste and smell dysfunction who exhibit hyposmia also exhibit decreased levels of cAMP and cGMP in nasal mucus compared to normal subjects. Since nasal mucus is the physiological medium which bathes the olfactory epithelium 26 , since both moieties play critical roles in both taste 9,10 and smell 11,12 function and in several aspects of neural function 27,28 , including acting as putative growth factors in both gustatory 9,10 and in olfactory systems 15,29 and in neural development in several systems [30][31][32] , these findings suggest that some physiological mechanism(s) related to function of these moieties and perhaps others moieties as well 33 relate to loss of olfactory acuity. This suggestion is confirmed by results in which treatment of these patients with PDE inhibitors increased these moieties in nasal mucus 19,34 and also improved their smell function.…”