简介: |
Ca2+ channels and calmodulin (CaM) are prominent hubs of signaling networks, extensively coordinated by feedback control. For example, each channel associates with its own CaM (but see PNAS 106:5135), acting as a Ca2+ sensor that regulates Ca2+ entry through channels. Because channels bind CaM avidly, every channel should possess CaM and exhibit regulation, regardless of biological fluctuations of CaM concentration. This would represent a significant form of concentration independence between Ca2+ channels and CaM. Here, we reveal significant exceptions to this autonomy, by combining electrophysiology to characterize channel regulation, with concurrent optical FRET sensor determination of free apoCaM concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context, into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of CaV1.3 and CaV1.4 channels include a distalcarboxy-tail module that functions like an enzyme inhibitor to retune channel affinity for apoCaM. In this configuration, natural CaM variations alter Ca2+ feedback gain, and the strength of competitive retuning is customized across channel subtypes (CaV1.3 versus CaV1.4), and species (rat versus human CaV1.3). Given the ubiquity of these channels, the corresponding connections between ambient CaM levels and Ca2+ entry via channels are broadly significant for Ca2+ homeostasis---presumed alterations of apoCaM levels in neurodegenerative conditions like Parkinson’s and Alzheimer’s are predicted to increase Ca2+ entry, potentially explaining the Ca2+ dysfunction underlying these diseases. Mechanistically, our extensions of enzyme inhibitor analysis argue well that the competitive retuning in holochannels indeed reflects competition between a single distal carboxy tail module and a single CaM molecule, both vying for IQ domain occupancy on channels. |
