Abstract
The large conductance, voltage- and calcium-dependent potassium (BK) channel serves as a major negative feedback regulator of calcium-mediated physiological processes and has been implicated in muscle dysfunction and neurological disorders. In addition to membrane depolarization, activation of the BK channel requires a rise in cytosolic calcium. Localization of the BK channel near calcium channels is therefore critical for its function. In a genetic screen designed to isolate novel regulators of the Caenorhabditis elegans BK channel, SLO-1, we identified ctn-1, which encodes an α-catulin homologue with homology to the cytoskeletal proteins α-catenin and vinculin. ctn-1 mutants resemble slo-1 loss-of-function mutants, as well as mutants with a compromised dystrophin complex. We determined that CTN-1 uses two distinct mechanisms to localize SLO-1 in muscles and neurons. In muscles, CTN-1 utilizes the dystrophin complex to localize SLO-1 channels near L-type calcium channels. In neurons, CTN-1 is involved in localizing SLO-1 to a specific domain independent of the dystrophin complex. Our results demonstrate that CTN-1 ensures the localization of SLO-1 within calcium nanodomains, thereby playing a crucial role in muscles and neurons.
Highlights
Precise control of membrane excitability, largely determined by ion channels, is of utmost importance for neuronal and muscle function
One mechanism to avoid detrimental calcium accumulation is to link the calcium increase with activation of calcium-dependent potassium ion channels, thereby reducing cell excitability and preventing further calcium influx. This negative feedback requires these potassium channels to be localized in close proximity to sites of calcium entry
In a Caenorhabditis elegans genetic screen, we identified a-catulin, known as a cytoskeletal regulatory protein in mammals, important for the localization of calcium-dependent potassium channels in both muscles and neurons
Summary
Precise control of membrane excitability, largely determined by ion channels, is of utmost importance for neuronal and muscle function. The regulation of ion channel localization, density and gating properties provides an effective way to control the excitability within these cells [1]. The large conductance, voltage- and calcium-dependent potassium BK channels ( called SLO-1 or Maxi-K) are uniquely gated by coincident calcium signaling and membrane depolarization [3,4]. This feature of BK channels provides a crucial negative feedback mechanism for calcium-induced functions, and plays an important role in determining the duration of action potentials [3]. BK channels are widely expressed in a variety of cell types and are implicated in many physiological processes, including the regulation of blood pressure [5], neuroendocrine signaling [6], smooth muscle tone [7], and neural network excitability [8,9]
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