Intestinal myofibroblasts have been implicated in the pathogenesis of chronic inflammatory conditions such as Crohn's disease via interactions with an elaborate network of cytokines, growth factors, and other inflammatory mediators. CXCR3 is a Galpha(i) protein-coupled receptor that binds the proinflammatory chemokines CXCL9, CXCL10, and CXCL11, which are released from the intestinal epithelium. The three CXCR3 ligands shared the ability to activate biochemical (e.g., PI3K and MAPK activation) and functional events (actin reorganization) in intestinal myofibroblasts. However, CXCL11 is unique in its ability to elevate intracellular calcium. Surprisingly, although CXCR3 mRNA is detectable in these myofibroblasts, there is no detectable surface expression of CXCR3. Furthermore, the biochemical responses and actin reorganization stimulated by the CXCR3 ligands in intestinal myofibroblasts are insensitive to the Galpha(i) inhibitor, pertussis toxin. This suggests either the existence of differential receptor coupling mechanisms in myofibroblasts for CXCR3 that are distinct from those observed in PBLs and/or that these cells express a modified or variant CXCR3 compared with the CXCR3 expressed on PBLs.

In adrenal glomerulosa cells, low threshold voltage-activated (T-type) calcium channels play a crucial role in coupling physiological variations of extracellular potassium to aldosterone biosynthesis. Angiotensin II markedly reduced the activity of these channels by shifting their activation curve toward positive voltage values. This inhibition of the channels resulted in a marked decrease of the cytosolic free calcium concentration maintained by potassium. This effect was abolished by losartan, a specific antagonist of the angiotensin II AT1 receptor. Hormone action on T-type channels appeared to be mediated by protein kinase C because 1) it was mimicked by phorbol ester and diacylglycerol, and 2) it was significantly reduced by decreasing protein kinase C activity with specific inhibitors such as chelerythrine chloride or a pseudosubstrate of the enzyme, as well as by protein kinase C down-regulation. Similarly, protein kinase C activation reduced the cytosolic calcium response to potassium and the steroidogenic action of this agonist. Low threshold T-type calcium channels therefore appear as potential sites for the modulation of steroidogenesis by protein kinase C in adrenal glomerulosa cells.

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