Abstract
While most large-conductance, calcium-, and voltage-activated potassium channels (BK or Maxi-K type) are blocked by the scorpion venom iberiotoxin, the so-called “type II” subtype has the property of toxin resistance. This property is uniquely mediated by channel assembly with one member of the BK accessory β subunit family, the neuron-enriched β4 subunit. This review will focus on current understanding of iberiotoxin-resistant, β4-containing BK channel properties and their function in the CNS. Studies have shown that β4 dramatically promotes BK channel opening by shifting voltage sensor activation to more negative voltage ranges, but also slows activation to timescales that theoretically preclude BK ability to shape action potentials (APs). In addition, β4 membrane trafficking is regulated through an endoplasmic retention signal and palmitoylation. More recently, the challenge has been to understand the functional role of the iberiotoxin-resistant BK subtype utilizing computational modeling of neurons and neurophysiological approaches. Utilizing iberiotoxin-resistance as a footprint for these channels, they have been identified in dentate gyrus granule neurons and in purkinje neurons of the cerebellum. In these neurons, the role of these channels is largely consistent with slow-gated channels that reduce excitability either through an interspike conductance, such as in purkinje neurons, or by replacing fast-gating BK channels that otherwise facilitate high frequency AP firing, such as in dentate gyrus neurons. They are also observed in presynaptic mossy fiber terminals of the dentate gyrus and posterior pituitary terminals. More recent studies suggest that β4 subunits may also be expressed in some neurons lacking iberiotoxin-resistant BK channels, such as in CA3 hippocampus neurons. Ongoing research using novel, specific blockers and agonists of BK/β4, and β4 knockout mice, will continue to move the field forward in understanding the function of these channels.
Highlights
While BK K+ channels are often identified using the scorpion venom iberiotoxin, seminal work by Rinehart and Levitan identified an iberiotoxin-resistant, slow-gated BK channel subtype from brain synaptosomal membranes (Reinhart et al, 1989; Reinhart and Levitan, 1995). The investigators classified this as the socalled “type II BK channel” which was in contrast to the more conventional iberiotoxin-sensitive type I, fast-gated BK channels
These results indicate that neurons may co-express distinct BK channel subtypes in different subcompartments, CEREBELLAR PURKINJE NEURONS BK channels likely have an important role in the cerebellum since knockout of the pore-forming subunit causes a profound ataxia in the mice (Meredith et al, 2004; Sausbier et al, 2004)
Our understanding of BK channel subtypes appears to be shifting from ascribing different BK channel subtypes in different neurons, to different BK channel subtypes cohabitating neurons
Summary
While BK K+ channels are often identified using the scorpion venom iberiotoxin, seminal work by Rinehart and Levitan identified an iberiotoxin-resistant, slow-gated BK channel subtype from brain synaptosomal membranes (Reinhart et al, 1989; Reinhart and Levitan, 1995). Later studies showed that while iberiotoxin-resistant BK channels are enriched in the pituitary terminals, BK channels of the hypothalamic somas that connect to these terminals are fast-gated, iberiotoxin-sensitive type I channels (Dopico et al, 1999) These results indicate that neurons may co-express distinct BK channel subtypes in different subcompartments, CEREBELLAR PURKINJE NEURONS BK channels likely have an important role in the cerebellum since knockout of the pore-forming subunit causes a profound ataxia in the mice (Meredith et al, 2004; Sausbier et al, 2004). Given that knockout of the β4 gene appears to allow greater trafficking of channels to the membrane (Shruti et al, 2012), one might speculate that FMRP may function to retain more β4 subunits in the ER in some neurons such as CA3, to allow BK channels to be fast-gated and more effectively shape action potentials
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