Nitric oxide acts independently of cGMP to modulate capacitative Ca2+ entry in mouse parotid acini

Carbachol- and thapsigargin-induced changes in cGMP accumulation were highl y dependent on extracellular Ca2+ in mouse parotid acini. Inhibition of nit ric oxide synthase (NOS) and soluble guanylate cyclase (sGC) resulted in co mplete inhibition of agonist-induced cGMP levels. NOS inhibitors reduced ag onist-induced Ca2+ release and capacitative Ca2+ entry, whereas the inhibit ion of sGC had no effect. The effects of NOS inhibition were not reversed b y 8-bromo-cGMP. The NO donor GEA-3162 increased cGMP levels blocked by the inhibition of sGC. GEA-3162-induced increases in Ca2+ release from ryanodin e-sensitive stores and enhanced capacitative Ca2+ entry, both of which were unaffected by inhibitors of sGC but reduced by NOS inhibitors. Results sup port a role for NO, independent of cGMP, in agonist-mediated Ca2+ release a nd Ca2+ entry. Data suggest that agonist-induced Ca2+ influx activates a Ca 2+-dependent NOS, leading to the production of NO and the release of Ca2+ f rom ryanodine-sensitive stares, providing a feedback loop by which store-de pleted Ca2+ channels are activated.