Abstract
Ion channels are present at specific levels within subcellular compartments of excitable cells. The regulation of ion channel trafficking and targeting is an effective way to control cell excitability. The BK channel is a calcium-activated potassium channel that serves as a negative feedback mechanism at presynaptic axon terminals and sites of muscle excitation. The C. elegans BK channel ortholog, SLO-1, requires an endoplasmic reticulum (ER) membrane protein for efficient anterograde transport to these locations. Here, we found that, in the absence of this ER membrane protein, SLO-1 channels that are seemingly normally folded and expressed at physiological levels undergo SEL-11/HRD1-mediated ER-associated degradation (ERAD). This SLO-1 degradation is also indirectly regulated by a SKN-1A/NRF1-mediated transcriptional mechanism that controls proteasome levels. Therefore, our data indicate that SLO-1 channel density is regulated by the competitive balance between the efficiency of ER trafficking machinery and the capacity of ERAD.
Highlights
The BK (KCa1.1, MaxiK, SLO1) channel is a large conductance calcium- and voltage-activated K+ channel, widely expressed in a variety of cell types
The SEL-11/HRD1 E3 ubiquitin ligase participates in the ER-associated degradation (ERAD) of functional SLO-1 channels
In a previous genetic study, we showed that a loss-of-function mutation in erg-28, a gene encoding an endoplasmic reticulum (ER) membrane protein, resulted in a marked reduction of SLO-1 channels in the presynaptic terminals and muscle excitation sites [21]
Summary
The BK (KCa1.1, MaxiK, SLO1) channel is a large conductance calcium- and voltage-activated K+ channel, widely expressed in a variety of cell types. The BK channel, a tetramer of pore-forming α subunits provides a negative feedback mechanism in response to membrane-depolarizing stimuli and increased cytosolic Ca2+ levels, preventing the excessive release of neurotransmitters from the presynaptic neuron or hyperexcitability in the muscle (Reviewed in [17]). In previous C. elegans genetic studies, we identified genes required for the localization of SLO-1, the BK channel ortholog, to the active zones of presynaptic terminals and muscle excitation sites [20,21]. Mutations in these genes caused diffuse SLO-1 channel localization but did not alter the overall level of SLO-1 channels, indicating that endocytosis at the plasma membrane is not a major regulatory mechanism for SLO-1 channel density. Known exceptions are found in only two sterol biosynthetic enzymes, whose degradation is regulated by specific signals [24,25,26]
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