Mice Lacking Either the PKGI or Pkgii Have Distinctive Phenotypes

Mice lacking either PKGI or PKGII have also been studied recently. PKGI-null mice have notable alterations in smooth muscle function. Motor activity in the gastrointestinal tract is highly disorganized and transit of foodstuffs through the gut is profoundly slowed. PKGI has been found in both the smooth muscle of the gastrointestinal tract as well as in some of the neurons of the enteric neural ganglia, and the absence of the PKGI from both of these tissues is likely to contribute to the dysfunction of gastrointestinal motility. Likewise, modulation of vascular smooth muscle function in these mice is impaired, consistent with the established importance of PKGI in promoting vasodilation. As a result, male PKGI-null mice have low ability to reproduce because of impaired relaxation of the smooth muscle in the vasculature of the penis, and the PKGI-null mice are somewhat hyper tensive and unresponsive to nitrovasodilators. Because systemic blood pressure is controlled by a multiplicity of factors, the absence of PKGI and the cGMP signaling through this enzyme is likely to be significantly compensated by adjustments in other signaling pathways; this results in the ability of the animals to maintain a relatively normal blood pressure even in the absence of PKGI.

The PKGII-null mice have a very different pheno-type from the PKGI-null mice, which is in agreement with the fact that the PKGI and PKGII are largely, if not entirely, expressed in separate tissues and involved in modulating different physiological processes. PKGII-knockout pups appear normal at birth, but defective developmental changes in the epiphy-seal growth plates retard bone growth, resulting in dwarfism in adults. These mice are insensitive to heat-stable enterotoxin-induced diarrhea that typically results from the phosphorylation of the CFTR-chloride channel in response to elevated cGMP. In normal mice, cGMP accumulates in response to the enterotoxin activation of guanylyl cyclase and in turn activates PKGII to increase chloride secretion and an accompanying water loss. This suggests that in the intestinal mucosa of normal animals, the sensitivity of the intestinal epithelium to the enterotoxin is mediated by PKGII. Gua-nylins activate the same subset of guanylyl cyclases and also modulate fluid homeostasis, and it is likely that PKGII mediates these effects as well.

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