Different pathways of calcium sensitization activated by receptor agonists and phorbol esters in vascular smooth muscle

Abstract

1 It has been shown that receptor agonists and activators of protein kinase C, phorbol esters, increase Ca2+ sensitivity of contractile elements in vascular smooth muscle. To discover if protein kinase C is involved in the agonist-mediated Ca2" sensitization, we examined the effects of receptor agonists in the rat isolated aorta in which protein kinase C activity had been diminished by pretreatment with phorbol 12-myristate 13-acetate for 24 h.2 In the aorta with protein kinase C activity, a high concentration (1 gM) of 12-deoxyphorbol 13-isobutyrate induced contraction and a low concentration (100 nM) potentiated high K+-induced contraction. In addition, prostaglandin F2. induced greater contractions than high K+ at a given cytosolic Ca2+ level. The maximally effective concentrations of noradrenaline and endothelin-1 also induced greater contraction than high K+. In the aorta without protein kinase C activity, the contraction induced by 12-deoxyphorbol 13-isobutyrate and its potentiation of the high K+-induced contraction were abolished. However, prostaglandin F2.., noradrenaline and endothelin-1 still induced a greater contraction than high K+.3 In the aorta without protein kinase C activity, noradrenaline, endothelin-l and prostaglandin F2,, but not 12-deoxyphorbol 13-isobutyrate, induced contractions in the presence of the Ca2+ channel blocker, verapamil, or in the absence of external Ca2+, by increasing Ca2+ sensitivify. 4 In the permeabilized preparations, inhibition of protein kinase C activity abolished the effect of potentiation of the Ca2'-induced contraction by 12-deoxyphorbol 13-isobutyrate although the potentiation of the contraction by prostaglandin F2C did not change.5 These results suggest that there are two pathways for Ca21 sensitization in rat aorta; a protein kinase C-dependent pathway which is activated by phorbol esters, and a protein kinase C-independent pathway which is activated by receptor agonists.

Time-Dependent Phenotypic and Contractile Changes of Pulmonary Artery in Chronic Hypoxia–Induced Pulmonary Hypertension

“…sensitization of contractile proteins in vascular smooth muscle (38,39), and this pathway is mediated by a rhoA-dependent process (40). We found here that basal active tonus was partly but significantly inhibited by Y-27632, a potent rho-kinase inhibitor.…”

Tyrosine phosphorylation as a convergent pathway of heterotrimeric G protein‐ and rho protein‐mediated Ca2+ sensitization of smooth muscle of rabbit mesenteric artery

“…In similar to GTP g S, phenylephrine and histamine enhanced the Ca 2+ -induced contractions without being modi®ed by the PKC inhibitors. While the possibility cannot ruled out that some receptor agonists may generate enough diacylglycerol to activate PKC to a level similar to that activated by phorbol esters and result in Ca 2+ sensitization through the PKC-dependent pathway, our conclusion that PKC has only a minor role, if any, in agonist-induced Ca 2+ sensitization is consistent with the results obtained in PKC-downregulated rat aorta (Hori et al, 1993). Therefore, it seems likely that phenylephrine and histamine also caused Ca 2+ sensitization through a PKCindependent pathway.…”

Possible Involvement of a Small G-Protein Sensitive to Exoenzyme C3 of Clostridium botulinum in the Regulation of Myofilament Ca2+ Sensitivity in β-Escin Skinned Smooth Muscle of Guinea Pig Ileum

“…It has been suggested that there are two pathways for Ca 21 sensitization in vascular smooth muscle: one is protein kinase C (PKC)-dependent and activated by phorbol esters, and the other is PKC-independent and activated by receptor agonists (26). Thus, it also remains to be clarified whether PKC is involved in the muscarinic Ca 2+-sensitizing effect in intestinal smooth muscle.…”