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Activity-Dependent Facilitation of Ca V 1.3 Calcium Channels Promotes KCa3.1 Activation in Hippocampal Neurons

2017; Society for Neuroscience; Volume: 37; Issue: 46 Linguagem: Inglês

10.1523/jneurosci.0967-17.2017

1529-2401

Giriraj Sahu, Hadhimulya Asmara, Fang‐Xiong Zhang, Gerald W. Zamponi, Ray W. Turner,

Neuroscience and Neuropharmacology Research

Ca V 1 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 V 1 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 V 1.3 channels, the scaffolding protein densin, and CaMKII could generate a facilitation of channel activity that outlasts a depolarizing stimulus. We found that Ca V 1.3 but not Ca V 1.2 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 V 1.3 L-CDF, we coexpressed the intermediate-conductance KCa3.1 potassium channel, revealing a strong functional coupling to Ca V 1.3 channel activity that was accentuated by densin and CaMKII. Moreover, the Ca V 1.3–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 V 1 channels by isradipine, a CaMKII blocker, and siRNA knockdown of densin, and spike frequency increased upon selective block of Ca V 1 channel conductance. The results are important in revealing a Ca V 1.3–densin–CaMKII interaction that extends the contribution of Ca V 1.3 calcium influx to a time frame well beyond a brief input train. SIGNIFICANCE STATEMENT Ca V 1 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 V 1.3 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 V 1.3 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 V 1.3-densin-CaMKII interaction, identifying an important role for Ca V 1.3 L-CDF in regulating neuronal excitability.