Sodium-activated potassium channels are functionally coupled to persistent sodium currents

We report a novel coupled system of sodium-activated potassium currents (I(KNa)) and persistent sodium currents (I(NaP)), the components of which are widely distributed throughout the brain. Its existence and importance has not been previously recognized. Although I(KNa) was known to exist in many cell types, the source of Na(+) which activates I(KNa) remained a mystery. We now show in single membrane patches generated from the somas of rat neurons that sodium influx through I(NaP) is sufficient for activation of K(Na) channels, without substantial contribution from the transient sodium current or bulk [Na(+)](i). I(NaP) was found to be active at cell membrane resting potentials, a finding that may explain why I(KNa) can be evoked from negative holding potentials. These results show an unanticipated role for I(NaP) in activating a negative feedback system countering the excitable effects I(NaP); the interrelatedness of I(NaP) and I(KNa) suggests new ways neurons can tune their excitability

GABA-B controls persistent Na+ current and coupled Na+-activated K+ current

AbstractThe GABA-B receptor is densely expressed throughout the brain and has been implicated in many CNS functions and disorders, including addiction, epilepsy, spasticity, schizophrenia, anxiety, cognitive deficits, and depression, as well as various aspects of nervous system development. How one GABA-B receptor is involved in so many aspects of CNS function remains unanswered. Activation of GABA-B receptors is normally thought to produce inhibitory responses in the nervous system, but puzzling contradictory responses exist. Here we report that in rat mitral cells of the olfactory bulb, GABA-B receptor activation inhibits both the persistent sodium current (INaP) and the sodium-activated potassium current (IKNa), which is coupled to it. We find that the primary effect of GABA-B activation is to inhibit INaP, which has the secondary effect of inhibiting IKNabecause of its dependence on persistent sodium entry for activation. This can have either a net excitatory or inhibitory effect depending on the balance of INaP/IKNacurrents in neurons. In the olfactory bulb, the cell bodies of mitral cells are densely packed with sodium-activated potassium channels. These channels produce a large IKNawhich, if constitutively active, would shunt any synaptic potentials traversing the soma before reaching the spike initiation zone. However, GABA-B receptor activation might have the net effect of reducing the IKNablocking effect, thus enhancing the effectiveness of synaptic potentials.</jats:p

A genetic variant of the sperm-specific SLO3 K+ channel has altered pH and Ca2+ sensitivities

To fertilize an oocyte, sperm must first undergo capacitation in which the sperm plasma membrane becomes hyperpolarized via activation of potassium (K(+)) channels and resultant K(+) efflux. Sperm-specific SLO3 K(+) channels are responsible for these membrane potential changes critical for fertilization in mouse sperm, and they are only sensitive to pH i However, in human sperm, the major K(+) conductance is both Ca(2+)- and pH i -sensitive. It has been debated whether Ca(2+)-sensitive SLO1 channels substitute for human SLO3 (hSLO3) in human sperm or whether human SLO3 channels have acquired Ca(2+) sensitivity. Here we show that hSLO3 is rapidly evolving and reveal a natural structural variant with enhanced apparent Ca(2+) and pH sensitivities. This variant allele (C382R) alters an amino acid side chain at a principal interface between the intramembrane-gated pore and the cytoplasmic gating ring of the channel. Because the gating ring contains sensors to intracellular factors such as pH and Ca(2+), the effectiveness of transduction between the gating ring and the pore domain appears to be enhanced. Our results suggest that sperm-specific genes can evolve rapidly and that natural genetic variation may have led to a SLO3 variant that differs from wild type in both pH and intracellular Ca(2+) sensitivities. Whether this physiological variation confers differences in fertility among males remains to be established.info:eu-repo/semantics/publishe

BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy

The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, with both changes in function becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The net cellular response from the five different types of channels comprising the molecular phenotype was a shift of -120 mV in the voltage required to activate half of the maximal current through BK channels, giving a net gain-of-function. The WT and homotetrameric mutant channels in the molecular phenotype were consistent with genetic codominance as each displayed properties of a channel arising from only one of the two alleles. The three types of hybrid channels in the molecular phenotype were consistent with partial dominance as their properties were intermediate between those of mutant and WT channels. A model in which BK channels randomly assemble from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation

Potassium channels in C. elegans

Ion channels are the "transistors" (electronic switches) of the brain that generate and propagate electrical signals in the aqueous environment of the brain and nervous system. Potassium channels are particularly important because, not only do they shape dynamic electrical signaling, they also set the resting potentials of almost all animal cells. Without them, animal life as we know it would not exist, much less higher brain function. Until the completion of the C. elegans genome sequencing project the size and diversity of the potassium channel extended gene family was not fully appreciated. Sequence data eventually revealed a total of approximately 70 genes encoding potassium channels out of the more than 19,000 genes in the genome. This seemed to be an unexpectedly high number of genes encoding potassium channels for an animal with a small nervous system of only 302 neurons. However, it became clear that potassium channels are expressed in all cell types, not only neurons, and that many cells express a complex palette of multiple potassium channels. All types of potassium channels found in C. elegans are conserved in mammals. Clearly, C. elegans is "simple" only in having a limited number of cells dedicated to each organ system; it is certainly not simple with respect to its biochemistry and cell physiology

The SLO3 sperm-specific potassium channel plays a vital role in male fertility

AbstractHere we show a unique example of male infertility conferred by a gene knockout of the sperm-specific, pH-dependent SLO3 potassium channel. In striking contrast to wild-type sperm which undergo membrane hyperpolarization during capacitation, we found that SLO3 mutant sperm undergo membrane depolarization. Several defects in SLO3 mutant sperm are evident under capacitating conditions, including impaired motility, a bent “hairpin” shape, and failure to undergo the acrosome reaction (AR). The failure of AR is rescued by valinomycin which hyperpolarizes mutant sperm. Thus SLO3 is the principal potassium channel responsible for capacitation-induced hyperpolarization, and membrane hyperpolarization is crucial to the AR

Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

Large conductance Ca(2+)-activated K(+) channels (BK channels) gate open in response to both membrane voltage and intracellular Ca(2+). The channel is formed by a central pore-gate domain (PGD), which spans the membrane, plus transmembrane voltage sensors and a cytoplasmic gating ring that acts as a Ca(2+) sensor. How these voltage and Ca(2+) sensors influence the common activation gate, and interact with each other, is unclear. A previous study showed that a BK channel core lacking the entire cytoplasmic gating ring (Core-MT) was devoid of Ca(2+) activation but retained voltage sensitivity (Budelli et al. 2013. Proc. Natl. Acad. Sci. USA. http://dx.doi.org/10.1073/pnas.1313433110). In this study, we measure voltage sensor activation and pore opening in this Core-MT channel over a wide range of voltages. We record gating currents and find that voltage sensor activation in this truncated channel is similar to WT but that the coupling between voltage sensor activation and gating of the pore is reduced. These results suggest that the gating ring, in addition to being the Ca(2+) sensor, enhances the effective coupling between voltage sensors and the PGD. We also find that removal of the gating ring alters modulation of the channels by the BK channel’s β1 and β2 subunits