Brenner, R. et al. BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat. Neurosci. 8, 1752-1759

Stanford University, Palo Alto, California, United States
Nature Neuroscience (Impact Factor: 16.1). 01/2006; 8(12):1752-9. DOI: 10.1038/nn1573
Source: PubMed


Synaptic inhibition within the hippocampus dentate gyrus serves a 'low-pass filtering' function that protects against hyperexcitability that leads to temporal lobe seizures. Here we demonstrate that calcium-activated potassium (BK) channel accessory beta4 subunits serve as key regulators of intrinsic firing properties that contribute to the low-pass filtering function of dentate granule cells. Notably, a critical beta4 subunit function is to preclude BK channels from contributing to membrane repolarization and thereby broaden action potentials. Longer-duration action potentials secondarily recruit SK channels, leading to greater spike frequency adaptation and reduced firing rates. In contrast, granule cells from beta4 knockout mice show a gain-of-function for BK channels that sharpens action potentials and supports higher firing rates. Consistent with breakdown of the dentate filter, beta4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy.

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Available from: Richard Aldrich, Oct 04, 2015
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    • "Finally, despite the hyperpolarizing effect of BK current, studies over the past decade have suggested a role for BK current in promoting repetitive firing and thus potentially opposing spike frequency adaptation, as we proposed in Figure 10. In rodent brain neurons, genetically induced (Brenner et al., 2005) or seizure-induced (Shruti et al., 2008) gain-of-function in BK channels is associated with elevated firing rate. On the other hand, pharmacological block of BK channels reduces firing rate in canine intracardiac neurons (Perez et al., 2013). "
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    ABSTRACT: Temporal patterns of spiking often convey behaviorally relevant information. Various synaptic mechanisms and intrinsic membrane properties can influence neuronal selectivity to temporal patterns of input. However, little is known about how synaptic mechanisms and intrinsic properties together determine the temporal selectivity of neuronal output. We tackled this question by recording from midbrain electrosensory neurons in mormyrid fish, in which the processing of temporal intervals between communication signals can be studied in a reduced in vitro preparation. Mormyrids communicate by varying interpulse intervals (IPIs) between electric pulses. Within the midbrain posterior exterolateral nucleus (ELp), the temporal patterns of afferent spike trains are filtered to establish single-neuron IPI tuning. We performed whole-cell recording from ELp neurons in a whole-brain preparation and examined the relationship between intrinsic excitability and IPI tuning. We found that spike frequency adaptation of ELp neurons was highly variable. Postsynaptic potentials (PSPs) of strongly adapting (phasic) neurons were more sharply tuned to IPIs than weakly adapting (tonic) neurons. Further, the synaptic filtering of IPIs by tonic neurons was more faithfully converted into variation in spiking output, particularly at short IPIs. Pharmacological manipulation under current- and voltage-clamp revealed that tonic firing is mediated by a fast, large-conductance Ca(2+)-activated K(+) (KCa) current (BK) that speeds up action potential repolarization. These results suggest that BK currents can shape the temporal filtering of sensory inputs by modifying both synaptic responses and PSP-to-spike conversion. Slow SK-type KCa currents have previously been implicated in temporal processing. Thus, both fast and slow KCa currents can fine-tune temporal selectivity.
    Frontiers in Cellular Neuroscience 09/2014; 8:286. DOI:10.3389/fncel.2014.00286 · 4.29 Impact Factor
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    • "Dissecting the functional roles of BK channels in the nervous system has been greatly aided by the availability of highly selective toxins (i.e., iberiotoxin) (Kaczorowski and Garcia, 1999) and small molecule inhibitors (e.g., penitrem A, paxilline, lolitrem B) (Knaus et al., 1994b; Imlach et al., 2008; Nardi and Olesen, 2008), along with the generation of genetically-engineered mice lacking either BKα or β subunits (Brenner et al., 2000b, 2005; Plüger et al., 2001; Meredith et al., 2004; Sausbier et al., 2004). Such strategies have revealed that the loss of neuronal BK current, either acutely or chronically, increases membrane excitability by decreasing the magnitude of the fAHP. "
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    ABSTRACT: Large conductance, Ca 2+ -activated K + (BK) channels represent an important pathway for the outward flux of K + ions from the intracellular compartment in response to membrane depolarization, and/or an elevation in cytosolic free [Ca 2+ ]. They are functionally expressed in a range of mammalian tissues (e.g., nerve and smooth muscles), where they can either enhance or dampen membrane excitability. The diversity of BK channel activity results from the considerable alternative mRNA splicing and post-translational modification (e.g., phosphorylation) of key domains within the pore-forming α subunit of the channel complex. Most of these modifications are regulated by distinct upstream cell signaling pathways that influence the structure and/or gating properties of the holo-channel and ultimately, cellular function. The channel complex may also contain auxiliary subunits that further affect channel gating and behavior, often in a tissue-specific manner. Recent studies in human and animal models have provided strong evidence that abnormal BK channel expression/function contributes to a range of pathologies in nerve and smooth muscle. By targeting the upstream regulatory events modulating BK channel behavior, it may be possible to therapeutically intervene and alter BK channel expression/function in a beneficial manner.
    Frontiers in Physiology 08/2014; 5(316). DOI:10.3389/fphys.2014.00316 · 3.53 Impact Factor
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    • "For BK channels, due to their large conductance, small changes in either the number or activity of the channel can dramatically modify potassium flux across the membrane with subsequent impact on cellular physiology. Indeed, disruption of BK channel function is linked to a variety of disorders of the vascular, nervous, endocrine and renal systems including hypertension, obesity, epilepsy, autism, incontinence and stress-related disorders (Brenner et al., 2000, 2005; Meredith et al., 2004; Sausbier et al., 2004, 2005; Du et al., 2005; Werner et al., 2005; Jiao et al., 2011; Deng et al., 2013). "
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    ABSTRACT: Mechanisms that control surface expression and/or activity of large conductance calcium-activated potassium (BK) channels are important determinants of their (patho)physiological function. Indeed, BK channel dysfunction is associated with major human disorders ranging from epilepsy to hypertension and obesity. S-acylation (S-palmitoylation) represents a major reversible, post-translational modification controlling the properties and function of many proteins including ion channels. Recent evidence reveals that both pore-forming and regulatory subunits of BK channels are S-acylated and control channel trafficking and regulation by AGC-family protein kinases. The pore-forming α-subunit is S-acylated at two distinct sites within the N- and C-terminus, each site being regulated by different palmitoyl acyl transferases (zDHHCs) and acyl thioesterases (APTs). S-acylation of the N-terminus controls channel trafficking and surface expression whereas S-acylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. S-acylation of the regulatory β4-subunit controls ER exit and surface expression of BK channels but does not affect ion channel kinetics at the plasma membrane. Furthermore, a significant number of previously identified BK-channel interacting proteins have been shown, or are predicted to be, S-acylated. Thus, the BK channel multi-molecular signaling complex may be dynamically regulated by this fundamental post-translational modification and thus S-acylation likely represents an important determinant of BK channel physiology in health and disease.
    Frontiers in Physiology 08/2014; 5:281. DOI:10.3389/fphys.2014.00281 · 3.53 Impact Factor
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