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Miloslav Kolaj - One of the best experts on this subject based on the ideXlab platform.

Sten Grillner - One of the best experts on this subject based on the ideXlab platform.

  • sodium dependent potassium channels of a slack like subtype contribute to the Slow Afterhyperpolarization in lamprey spinal neurons
    The Journal of Physiology, 2007
    Co-Authors: Peter Wallen, Brita Robertson, Lorenzo Cangiano, Peter Low, Arin Bhattacharjee, Leonard K Kaczmarek, Sten Grillner
    Abstract:

    The Slow Afterhyperpolarization (sAHP) following the action potential is the main determinant of spike frequency regulation. The sAHP after single action potentials in neurons of the lamprey locomotor network is largely due to calcium-dependent K+ channels (80%), activated by calcium entering the cell during the spike. The residual (20%) component becomes prominent during high level activity (50% of the sAHP). It is not Ca2+ dependent, has a reversal potential like that of potassium, and is not affected by chloride injection. It is not due to rapid activation of Na+/K+-ATPase. This non-KCa-sAHP is reduced markedly in amplitude when sodium ions are replaced by lithium ions, and is thus sodium dependent. Quinidine also blocks this sAHP component, further indicating an involvement of sodium-dependent potassium channels (KNa). Modulators tested do not influence the KNa-sAHP amplitude. Immunofluorescence labelling with an anti-Slack antibody revealed distinct immunoreactivity of medium-sized and large neurons in the grey matter of the lamprey spinal cord, suggesting the presence of a Slack-like subtype of KNa channel. The results strongly indicate that a KNa potassium current contributes importantly to the sAHP and thereby to neuronal frequency regulation during high level burst activity as during locomotion. This is, to our knowledge, the first demonstration of a functional role for the Slack gene in contributing to the Slow AHP.

  • 5-HT Modulation of identified segmental premotor interneurons in the lamprey spinal cord.
    Journal of neurophysiology, 2006
    Co-Authors: Zoltán Biró, Russell H. Hill, Sten Grillner
    Abstract:

    Ipsilaterally projecting spinal excitatory interneurons (EINs) generate the hemisegmental rhythmic locomotor activity in lamprey, while the commissural interneurons ensure proper left-right alternation. 5-HT is a potent modulator of the locomotor rhythm and is endogenously released from the spinal cord during fictive locomotion. The effect of 5-HT was investigated for three segmental premotor interneuron types: EINs, commissural excitatory and commissural inhibitory interneurons. All three types of interneurons produced chemical postsynaptic potentials in motoneurons, but only those from EINs had an electrical component. The effect of 5-HT was studied on the Slow Afterhyperpolarization, involved in spike frequency regulation, and on the segmental synaptic transmission to motoneurons. 5-HT induced a reduction in the Slow Afterhyperpolarization and a depression of synaptic transmission in all three types of segmental interneurons. Thus 5-HT is a very potent modulator of membrane properties and synaptic transmission of last-order segmental premotor interneurons. Such modulation of locomotor network interneurons can partially account for the observed effects of 5-HT on the swimming pattern in lamprey.

  • Apamin blocks the Slow AHP in lamprey and delays termination of locomotor bursts.
    Neuroreport, 1992
    Co-Authors: Russel Hill, J. L. Schotland, Toshiya Matsushima, Sten Grillner
    Abstract:

    The effects of apamin on the Slow Afterhyperpolarization (sAHP) in spinal neurones and on the frequency of rhythmic bursting during fictive locomotion were investigated in the lamprey spinal cord in vitro. Apamin, which is a selective blocker of a small conductance KCa channel responsible for the sAHP in many types of neurones, was also found to reduce the sAHP in lamprey neurones. The summation of the sAHP is considered to be an important burst terminating factor in the spinal locomotor network and thereby to regulate the frequency of fictive locomotion. In support of this view, apamin was found to reduce the frequency of rhythmic bursting during fictive locomotion induced by kainate and NMDA. Serotonin, which has previously been shown to reduce the sAHP and Slow the rate of rhythmic bursting, may therefore act, at least in part, on apamin-sensitive KCa channels.

Anastassios V Tzingounis - One of the best experts on this subject based on the ideXlab platform.

  • the specific Slow Afterhyperpolarization inhibitor ucl2077 is a subtype selective blocker of the epilepsy associated kcnq channels
    Molecular Pharmacology, 2010
    Co-Authors: Heun Soh, Anastassios V Tzingounis
    Abstract:

    Mutations in members of the KCNQ channel family underlie multiple diseases affecting the nervous and cardiovascular systems. Despite their clinical relevance, research into these channels is limited by the lack of subtype-selective inhibitors, making it difficult to differentiate the physiological function of each family member in vivo. We have proposed that KCNQ channels might partially underlie the calcium-activated Slow Afterhyperpolarization (sAHP), a neuronal conductance whose molecular components are uncertain. Here, we investigated whether 3-(triphenylmethylaminomethyl)pyridine (UCL2077), identified previously as an inhibitor of the sAHP in neurons, acts on members of the KCNQ family expressed in heterologous cells. We found that 3 μM UCL2077 strongly inhibits KCNQ1 and KCNQ2 channels and weakly blocks KCNQ4 channels in a voltage-independent manner. In contrast, UCL2077 potentiates KCNQ5 channels at more positive membrane potentials, with little effect at negative membrane potentials. We found that the effect of UCL2077 on KCNQ3 is bimodal: currents are enhanced at negative membrane potentials and inhibited at positive potentials. We found that UCL2077 facilitates KCNQ3 currents by inducing a leftward shift in the KCNQ3 voltage-dependence, a shift dependent on tryptophan 265. Finally, we show that UCL2077 has intermediate effects on KCNQ2/3 heteromeric channels compared with KCNQ2 and KCNQ3 homomers. Together, our data demonstrate that UCL2077 acts on KCNQ channels in a subtype-selective manner. This feature should make UCL2077 a useful tool for distinguishing KCNQ1 and KCNQ2 from less-sensitive KCNQ family members in neurons and cardiac cells in future studies.

  • the kcnq5 potassium channel mediates a component of the Afterhyperpolarization current in mouse hippocampus
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Anastassios V Tzingounis, Matthias Heidenreich, Tatjana Kharkovets, Guillermo Spitzmaul, Henrik S Jensen, Roger A Nicoll, Thomas J. Jentsch
    Abstract:

    Mutations in KCNQ2 and KCNQ3 voltage-gated potassium channels lead to neonatal epilepsy as a consequence of their key role in regulating neuronal excitability. Previous studies in the brain have focused primarily on these KCNQ family members, which contribute to M-currents and Afterhyperpolarization conductances in multiple brain areas. In contrast, the function of KCNQ5 (Kv7.5), which also displays widespread expression in the brain, is entirely unknown. Here, we developed mice that carry a dominant negative mutation in the KCNQ5 pore to probe whether it has a similar function as other KCNQ channels. This mutation renders KCNQ5dn-containing homomeric and heteromeric channels nonfunctional. We find that Kcnq5dn/dn mice are viable and have normal brain morphology. Furthermore, expression and neuronal localization of KCNQ2 and KCNQ3 subunits are unchanged. However, in the CA3 area of hippocampus, a region that highly expresses KCNQ5 channels, the medium and Slow Afterhyperpolarization currents are significantly reduced. In contrast, neither current is affected in the CA1 area of the hippocampus, a region with low KCNQ5 expression. Our results demonstrate that KCNQ5 channels contribute to the Afterhyperpolarization currents in hippocampus in a cell type-specific manner.

  • Contribution of KCNQ2 and KCNQ3 to the medium and Slow Afterhyperpolarization currents
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Anastassios V Tzingounis, Roger A Nicoll
    Abstract:

    Benign familial neonatal convulsion (BNFC) is a neurological disorder caused by mutations in the potassium channel genes KCNQ2 and KCNQ3, which are thought to contribute to the medium Afterhyperpolarization (mAHP). Despite their importance in normal brain function, it is unknown whether they invariably function as heteromeric complexes. Here, we examined the contribution of KCNQ3 and KCNQ2 in mediating the apamin-insensitive mAHP current (ImAHP) in hippocampus. The ImAHP was not impaired in CA1 pyramidal neurons from mice genetically deficient for either KCNQ3 or KCNQ2 but was reduced ≈50% in dentate granule cells. While recording from KCNQ-deficient mice, we observed that the calcium-activated Slow Afterhyperpolarization current (IsAHP) was also reduced in dentate granule cells, suggesting that KCNQ channels might also contribute to this potassium current whose molecular identity is unknown. Further pharmacological and molecular experiments manipulating KCNQ channels provided evidence in support of this possibility. Together our data suggest that multiple KCNQ subunit compositions can mediate the ImAHP, and that the very same subunits may also contribute to the IsAHP. We also present data suggesting that the neuronal calcium sensor protein hippocalcin may allow for these dual signaling processes.

  • Hippocalcin gates the calcium activation of the Slow Afterhyperpolarization in hippocampal pyramidal cells.
    Neuron, 2007
    Co-Authors: Anastassios V Tzingounis, Masaaki Kobayashi, Ken Takamatsu, Roger A Nicoll
    Abstract:

    Summary In the brain, calcium influx following a train of action potentials activates potassium channels that mediate a Slow Afterhyperpolarization current (I sAHP ). The key steps between calcium influx and potassium channel activation remain unknown. Here we report that the key intermediate between calcium and the sAHP channels is the diffusible calcium sensor hippocalcin. Brief depolarizations sufficient to activate the I sAHP in wild-type mice do not elicit the I sAHP in  hippocalcin knockout mice. Introduction of hippocalcin in cultured hippocampal neurons leads to a pronounced I sAHP , while neurons expressing a hippocalcin mutant lacking N-terminal myristoylation exhibit a small I sAHP that is similar to that recorded in uninfected neurons. This implies that hippocalcin must bind to the plasma membrane to mediate its effects. These findings support a model in which the calcium sensor for the sAHP channels is not preassociated with the channel complex.

Li Zhang - One of the best experts on this subject based on the ideXlab platform.

J B Furness - One of the best experts on this subject based on the ideXlab platform.

  • regulation of the Slow Afterhyperpolarization in enteric neurons by protein kinase a
    Autonomic Neuroscience: Basic and Clinical, 2006
    Co-Authors: Craig B. Neylon, Christopher Fowler, J B Furness
    Abstract:

    Abstract The Slow after-hyperpolarization (sAHP) following the action potential is an important determinant of the firing patterns of enteric neurons. The channel responsible for the sAHP thus serves as a critical control point at which neurotransmitters and inflammatory mediators modulate gut motility. Many of these receptor-evoked pathways are known to inhibit the sAHP and, thus, excite enteric neurons. They act through protein kinase A (PKA) which is a strong inhibitor of the sAHP current while protein phosphatases enhance the current. Increasing evidence suggests that the sAHP is mediated by the opening of intermediate-conductance Ca-activated potassium (IK) channels. This neuronal IK channel, previously known to be expressed in a variety of non-excitable cells, is strongly influenced by protein kinases. Investigation of the molecular basis for the modulation of IK channels by protein phosphorylation indicates that there are multiple mechanisms of channel control. Inhibition of channel activity by PKA involves phosphorylation sites located within the calmodulin-binding domain of the channel. The localization of these sites within the region involved in Ca2 + activation suggests that PKA-mediated phosphorylation of the channel opposes the conformational changes caused by binding of Ca/calmodulin, which would otherwise lead to opening of the channel. We suggest that the channel exists as a macromolecular complex involving calmodulin, protein kinases, protein phosphatase and possibly other proteins. The regulation of the channel through kinases and phophatases results in exquisite control of neuronal firing and subsequent modulation of enteric reflexes.

  • regulation of k channels underlying the Slow Afterhyperpolarization in enteric Afterhyperpolarization generating myenteric neurons role of calcium and phosphorylation
    Clinical and Experimental Pharmacology and Physiology, 2002
    Co-Authors: Fivos Vogalis, Craig B. Neylon, John R. Harvey, J B Furness
    Abstract:

    1. Myenteric Afterhyperpolarization-generating myenteric (AH) neurons serve as intrinsic primary afferent neurons of the enteric nervous system and generate prolonged or Slow afterhyperpolarizing potentials (Slow AHP). The Slow AHP is generated by an increase in a Ca2+-activated K+ conductance (gK-Ca) and is inhibited by enteric neurotransmitters leading to increased excitability. 2. Using cell-attached patch-clamp recordings from AH neurons, we have shown that K+ channels with an intermediate unitary conductance (IK channels) open following action potential firing. 3. In excised patches from AH neurons, we have identified an IK-like channel that can be activated by submicromolar levels of cytoplasmic Ca2+ and is not voltage dependent. 4. Application of the catalytic subunit of cAMP-dependent protein kinase to the cytoplasmic surface of inside-out patches inhibits the opening of IK-like channels previously activated by Ca2+. 5. The IK-like channels are resistant to external tetraethylammonium (5 mmol/L) and apamin (0.3-1 micro mol/L), but are inhibited by clotrimazole (10 micro mol/L). 6. Our present data support the idea that an increase in the open probability of IK-like channels in AH neurons following an increase in cytoplasmic [Ca2+] is responsible for the Slow AHP and their opening is modulated by kinases.

  • tea and apamin resistant kca channels in guinea pig myenteric neurons Slow ahp channels
    The Journal of Physiology, 2002
    Co-Authors: Fivos Vogalis, John R. Harvey, J B Furness
    Abstract:

    The patch-clamp technique was used to record from intact ganglia of the guinea-pig duodenum in order to characterize the K+ channels that underlie the Slow Afterhyperpolarization (Slow AHP) of myenteric neurons. Cell-attached patch recordings from Slow AHP-generating (AH) neurons revealed an increased open probability (Po) of TEA-resistant K+ channels following action potentials. The Po increased from 100 ms in the absence of Ca2+ to about 7 ms in the presence of submicromolar cytoplasmic Ca2+. The Ca2+-insensitive closed dwell time had a time constant of about 1 ms. We propose that these small-to-intermediate conductance TEA- and apamin-resistant Ca2+-activated K+ channels are the channels that are primarily responsible for the Slow AHP in myenteric AH neurons.

  • electrophysiological and morphological classification of myenteric neurons in the proximal colon of the guinea pig
    Neuroscience, 1994
    Co-Authors: J P Messenger, J C Bornstein, J B Furness
    Abstract:

    Abstract Intracellular recordings were made from myenteric neurons in the proximal colon of the guinea-pig. The electrical behaviour of the neurons in response to intracellular depolarizing current pulses, and to internodal strand stimulation, was recorded. The intracellular electrode contained the intracellular marker biocytin which was injected into impaled neurons for subsequent histochemistry. Proximal colon myenteric neurons displayed electrophysiological properties similar to myenteric neurons in the small intestine, and were classified as either AH- or S-neurons. AH-neurons were characterized by the presence of a Slow Afterhyperpolarization following an action potential. Internodal strand stimulation evoked Slow excitatory synaptic potentials in five out of six AH-neurons tested, but did not evoke fast excitatory synaptic potentials in 26 AH-neurons tested. S-neurons lacked a Slow Afterhyperpolarization, but internodal strand stimulation evoked fast excitatory synaptic potentials in all 113 neurons and Slow excitatory synaptic potentials in seven out of 17 tested. A subpopulation of AH-neurons displayed a rhythmic oscillation in membrane potential which could be triggered by an action potential. S-neurons could be subdivided into those that fired tonically and those that fired phasically in response to long depolarizing current pulses. About 80% of the AH-neurons were immunoreactive for calbindin, as were 10% of S-neurons. A further 17% of S-neurons, but no AH neurons, were calretinin immunoreactive. Morphological analysis of filled neurons revealed eight distinct classes. Neurons electrophysiologically classified as AH typically had a large, oval soma and several long tapering processes. Processes of AH-neurons branched into many adjacent ganglia. Almost all S-neurons were uniaxonal and many axons ended in an expansion bulb in the myenteric plexus. S-neurons typically had broad, lamellar processes, or short, spiny processes. Roughly equal proportions of S-neurons had oral or anal projections. However, almost all S-neurons that were immunoreactive for calbindin or calretinin projected orally. The results indicate that myenteric neurons in the proximal colon of the guinea-pig are electrophysiologically similar to myenteric neurons in the small intestine, but there are a greater number of morphological and chemical categories.