Abstract
Large-conductance, calcium-activated K+ (BK) channels are widely distributed throughout the nervous system and play an essential role in regulation of action potential duration and firing frequency, along with neurotransmitter release at the presynaptic terminal. We have previously demonstrated that select mutations in cysteine string protein (CSPα), a presynaptic J-protein and co-chaperone, increase BK channel expression. This observation raised the possibility that wild-type CSPα normally functions to limit neuronal BK channel expression. Here we show by Western blot analysis of transfected neuroblastoma cells that when BK channels are present at elevated levels, CSPα acts to reduce expression. Moreover, we demonstrate that the accessory subunits, BKβ4 and BKβ1 do not alter CSPα-mediated reduction of expressed BKα subunits. Structure-function analysis reveals that the N-terminal J-domain of CSPα is critical for the observed regulation of BK channels levels. Finally, we demonstrate that CSPα limits BK current amplitude, while the loss-of-function homologue CSPαHPD-AAA increases BK current. Our observations indicate that CSPα has a role in regulating synaptic excitability and neurotransmission by limiting expression of BK channels.
Highlights
Cysteine string protein (CSPa) is a presynaptic co-chaperone for Hsc70 that protects neurons from degeneration and synaptic loss [1]
Mutations of CSPa in humans are associated with adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL), which is a progressive neurodegenerative disorder characterized by psychiatric manifestations, seizures, progressive dementia and motor impairment [3,4,5]
Robust BK Channel Expression is Reduced by CSPa We have recently reported that interference of CSPa activity, either by genetic disruption (i.e. CSPa2/2 mice) or expression of dysfunctional CSPa in a neuronal cell line, is associated with a significant elevation of BK channel density at the cell surface [10]
Summary
Cysteine string protein (CSPa) is a presynaptic co-chaperone for Hsc that protects neurons from degeneration and synaptic loss [1]. CSPa is a synaptic vesicle-associated protein bearing a characteristic J domain, as well as a cysteine rich ‘string’ region [2]. Mutations of CSPa in humans are associated with adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL), which is a progressive neurodegenerative disorder characterized by psychiatric manifestations, seizures, progressive dementia and motor impairment [3,4,5]. Disruption of the CSPa gene causes impaired presynaptic neurotransmission in Drosophila melanogaster [6] and fulminant neurodegeneration in mice [1,7]. In CSPa null mice, synapse loss occurs in an age- [1] and activity-dependent manner [8,9]. The cellular mechanisms that underlie CSPa’s neuroprotective function remain to be established
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