Iberiotoxin-sensitive large conductance Ca2+-dependent K+ (BK) channels regulate the spike configuration in the burst firing of cerebellar Purkinje neurons
“…This fast inactivation was later shown to be conferred by the N-terminal residues of BK β2 subunit (Wallner, Meera, & Toro, 1999; Xia, Ding, & Lingle, 1999). Using this unique inactivating property, β2-containing BK channels have been identified in hippocampus, neocortex, and lateral amygdala pyramidal neurons, as well as in cerebellar Purkinje cells and dorsal root ganglion (DRG) neurons (Faber & Sah, 2003; Haghdoost-Yazdi, Janahmadi, & Behzadi, 2008; Hicks & Marrion, 1998; Li et al, 2007; McLarnon, 1995; Sun, Gu, & Haddad, 2003). There is, to the best of our knowledge, no ligand that selectively discriminates β2-containing BK channels.…”
Section: Expression Patterns Of Bk Channel Subunits In the Cnsmentioning
Large conductance Ca2+- and voltage-activated K+ (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca2+ concentrations. In neurons, they regulate the timing and duration of K+ influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals. In addition, BK channels located in astrocytes and arterial myocytes modulate cerebral blood flow. Not surprisingly, both loss and gain of BK channel function have been associated with CNS disorders such as epilepsy, ataxia, mental retardation, and chronic pain. On the other hand, the neuroprotective role played by BK channels in a number of pathological situations could potentially be leveraged to correct neurological dysfunction.
“…This fast inactivation was later shown to be conferred by the N-terminal residues of BK β2 subunit (Wallner, Meera, & Toro, 1999; Xia, Ding, & Lingle, 1999). Using this unique inactivating property, β2-containing BK channels have been identified in hippocampus, neocortex, and lateral amygdala pyramidal neurons, as well as in cerebellar Purkinje cells and dorsal root ganglion (DRG) neurons (Faber & Sah, 2003; Haghdoost-Yazdi, Janahmadi, & Behzadi, 2008; Hicks & Marrion, 1998; Li et al, 2007; McLarnon, 1995; Sun, Gu, & Haddad, 2003). There is, to the best of our knowledge, no ligand that selectively discriminates β2-containing BK channels.…”
Section: Expression Patterns Of Bk Channel Subunits In the Cnsmentioning
Large conductance Ca2+- and voltage-activated K+ (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca2+ concentrations. In neurons, they regulate the timing and duration of K+ influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals. In addition, BK channels located in astrocytes and arterial myocytes modulate cerebral blood flow. Not surprisingly, both loss and gain of BK channel function have been associated with CNS disorders such as epilepsy, ataxia, mental retardation, and chronic pain. On the other hand, the neuroprotective role played by BK channels in a number of pathological situations could potentially be leveraged to correct neurological dysfunction.
“…The large-conductance, calcium-activated (BK) and voltage-dependent (KV) potassium channels are important regulators of electrical signaling in the heart and brain, arterial tone, electrical tuning in cochlear hair cells, uterine contractions, hormone release, and lymphocyte proliferation [2][3][4][5][6][7][8][9][10]. Much of our understanding of how BK and KV channels regulate these processes depends on selective inhibition with peptide neurotoxins, a-KTx, that occlude the outer pore [11][12][13][14][15][16][17]. The a-KTx peptides display a broad range of affinity for different types of potassium channels that allows some of these a-KTx to selectively inhibit certain types of potassium channels [12].…”
The alpha-KTx peptide toxins inhibit different types of potassium channels by occluding the outer channel pore composed of four identical alpha subunits. The large-conductance, calcium-activated (BK or Slo1) and voltage-dependent (KV) potassium channels differ in their specificity for the different alpha-KTx subfamilies. While many different alpha-KTx subfamilies of different sizes inhibit KV1 channels with high affinity, only one subfamily, alpha-KTx 1.x, inhibits BK channels with high affinity. Two solvent-exposed regions of the outer pore that influence alpha-KTx binding, the turret and loop, display high sequence variability among different potassium channels and may contribute to differences in alpha-KTx specificity. While these alpha-KTx domains have been studied in KV1 channels, little is known about the corresponding BK alpha-KTx domains. To define alpha-KTx sites in the BK outer pore, we examined the effect of 19 outer pore mutations on specific binding of 125I-labeled iberiotoxion (IbTX or alpha-KTx 1.3) and on their cell-surface expression. Similar to alpha-KTx sites in the Shaker KV1 loop, site-directed mutations in the BK loop disrupted specific IbTX binding. In contrast, mutations in the BK turret region revealed three novel alpha-KTx sites, Q267, N268, and L272, which are distinct from alpha-KTx sites in the KV1 turret. The BK turret region shows no sequence identity with KV1 and MthK turrets of known 3D structure. To define the BK turret, we used secondary structure prediction methods that incorporated information from sequence alignment of 30 different Slo1 and Slo3 turret sequences from 5 of the 7 major animal phyla representing 27 different species. Results of this analysis suggest that the BK turret contains 18 amino acids and is defined by a cluster of strictly conserved polar residues at the N-terminal side of the turret. Thus, the BK turret is predicted to have six more amino acids than the KV1 turret. Results of this work suggest that BK and KV1 outer pores have a similar alpha-KTx domain in the loop preceding the inner helix, but that the BK turret comprises a unique alpha-KTx interaction surface that likely contributes to the exclusive selectivity of BK channels for alpha-KTx1.x toxins.
“…Large conductance, calcium-activated K + channels (BK channels) are widely distributed throughout the CNS, and play an important role in regulating neuronal action potential duration, the extent of fast after-hyperpolarization and burst firing frequency123. BK channels are also prominent in the pre-synaptic membrane, where they regulate the magnitude and timing of depolarization-evoked calcium influx, thereby influencing neurotransmitter release at the synapse45678.…”
Large-conductance, calcium-activated-K+ (BK) channels are widely distributed throughout the nervous system, where they regulate action potential duration and firing frequency, along with presynaptic neurotransmitter release. Our recent efforts to identify chaperones that target neuronal ion channels have revealed cysteine string protein (CSPα) as a key regulator of BK channel expression and current density. CSPα is a vesicle-associated protein and mutations in CSPα cause the hereditary neurodegenerative disorder, adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL). CSPα null mice show 2.5 fold higher BK channel expression compared to wild type mice, which is not seen with other neuronal channels (i.e. Cav2.2, Kv1.1 and Kv1.2). Furthermore, mutations in either CSPα's J domain or cysteine string region markedly increase BK expression and current amplitude. We conclude that CSPα acts to regulate BK channel expression, and consequently CSPα-associated changes in BK activity may contribute to the pathogenesis of neurodegenerative disorders, such as ANCL.
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