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Regulation of Cation Channel Voltage and Ca²⁺ Dependence by Multiple Modulators

Department of Physiology, Queen's University, Kingston, Ontario, Canada

Submitted 21 January 2009; accepted in final form 15 April 2009

Ion channel regulation is key to controlling neuronal excitability. However, the extent that modulators and gating factors interact to regulate channels is less clear. For Aplysia, a nonselective cation channel plays an essential role in reproduction by driving an afterdischarge in the bag cell neurons to elicit egg-laying hormone secretion. We examined the regulation of cation channel voltage and Ca²⁺ dependence by protein kinase C (PKC) and inositol trisphosphate (IP₃)—two prominent afterdischarge signals. In excised, inside-out patches, the channel remained open longer and reopened more often with depolarization from –90 to +30 mV. As previously reported, PKC could closely associate with the channel and increase activity at –60 mV. We now show that, following the effects of PKC, voltage dependence was shifted to the left (essentially enhanced), particularly at more negative voltages. Conversely, the voltage dependence of channels lacking PKC was shifted to the right (essentially suppressed). Predictably, activity was increased at all Ca²⁺ concentrations following the effects of PKC; nevertheless, Ca²⁺ dependence was actually shifted to the right. Moreover, whereas IP₃ did not alter activity at –60 mV, it drastically shifted Ca²⁺ dependence to the right—an outcome largely reversed by PKC. With respect to the afterdischarge, these data suggest PKC initially upregulates the channel by direct gating and shifting voltage dependence to the left. Subsequently, PKC and IP₃ attenuate the channel by suppressing Ca²⁺ dependence. This ensures hormone delivery by allowing afterdischarge initiation and maintenance but also prevents interminable bursting. Similar regulatory interactions may be used by other neurons to achieve diverse outputs.