AN INSULIN-SENSITIVE CATION CHANNEL CONTROLS [NA-REGULATED NA+ AND CA2+ ENTRY(](I) VIA [CA2+](O))

The insulin-stimulated cation channel previously identified in patch-c lamped muscle preparations is here shown to be responsible for bulk Na + entry into the cell. The mainly Na+ current of the channel was shown to be accompanied by an inhibitory Ca2+ component responsible for osc illations. Here, using quantitative fluorescence imaging of Fura-2- an d SBFI-loaded soleus muscle, we measure changes in [Na+](i) and [Ca2+] (i) related to channel function. Insulin increased [Na+](i) and [Ca+]( i) in a transient spike of < 1-min duration. There was a momentary dip in [Na+]i related to inhibition of the channel by the Ca2+ spike, and changes in external Ca2+ were shown to alter [Na+](i) via the cation channel, all effects being blocked by the specific channel inhibitor m u-conotoxin, but not by tetrodotoxin. The [Ca2+](i) spike could also b e induced by 8-bromo cyclic-guanosine 5'-monophosphate, an analogue of the channel-activator cyclic-guanosine 5'-monophosphate (cGMP). In ad dition it was noted that insulin reduced the [Ca2+](i) rise upon subse quent muscle depolarization by a factor of 3.5. Insulin could be subst ituted with phorbol ester for the same effect and HA1004, a protein ki nase inhibitor, blocked the reduction.