Activity-Dependent Facilitation of Ca_V1.3 Calcium Channels Promotes KCa3.1 Activation in Hippocampal Neurons

Ca_V1 L-type calcium channels are key to regulating neuronal excitability, with the range of functional roles enhanced by interactions with calmodulin, accessory proteins, or CaMKII that modulate channel activity. In hippocampal pyramidal cells, a prominent elevation of Ca_V1 activity is apparent in late channel openings that can last for seconds following a depolarizing stimulus train. The current study tested the hypothesis that a reported interaction among Ca_V1.3 channels, the scaffolding protein densin, and CaMKII could generate a facilitation of channel activity that outlasts a depolarizing stimulus. We found that Ca_V1.3 but not Ca_V1.2 channels exhibit a long-duration calcium-dependent facilitation (L-CDF) that lasts up to 8 s following a brief 50 Hz stimulus train, but only when coexpressed with densin and CaMKII. To test the physiological role for Ca_V1.3 L-CDF, we coexpressed the intermediate-conductance KCa3.1 potassium channel, revealing a strong functional coupling to Ca_V1.3 channel activity that was accentuated by densin and CaMKII. Moreover, the Ca_V1.3-densin-CaMKII interaction gave rise to an outward tail current of up to 8 s duration following a depolarizing stimulus in both tsA-201 cells and male rat CA1 pyramidal cells. A slow afterhyperpolarization in pyramidal cells was reduced by a selective block of Ca_V1 channels by isradipine, a CaMKII blocker, and siRNA knockdown of densin, and spike frequency increased upon selective block of Ca_V1 channel conductance. The results are important in revealing a Ca_V1.3-densin-CaMKII interaction that extends the contribution of Ca_V1.3 calcium influx to a time frame well beyond a brief input train.SIGNIFICANCE STATEMENT Ca_V1 L-type calcium channels play a key role in regulating the output of central neurons by providing calcium influx during repetitive inputs. This study identifies a long-duration calcium-dependent facilitation (L-CDF) of Ca_V1.3 channels that depends on the scaffolding protein densin and CaMKII and that outlasts a depolarizing stimulus by seconds. We further show a tight functional coupling between Ca_V1.3 calcium influx and the intermediate-conductance KCa3.1 potassium channel that promotes an outward tail current of up to 8 s following a depolarizing stimulus. Tests in CA1 hippocampal pyramidal cells reveal that a slow AHP is reduced by blocking different components of the Ca_V1.3-densin-CaMKII interaction, identifying an important role for Ca_V1.3 L-CDF in regulating neuronal excitability.