1,032 research outputs found
Block of Voltage-Dependent Calcium Channels by Aliphatic Monoamines
No full textAbstractWe have recently identified farnesol, an intermediate in the mevalonate pathway, as a potent endogenous modulator and blocker of N-type calcium channels (Roullet, J. B., R. L. Spaetgens, T. Burlingame, and G. W. Zamponi. 1999. J. Biol. Chem. 274:25439–25446). Here, we investigate the action of structurally related compounds on various types of voltage-dependent Ca2+ channels transiently expressed in human embryonic kidney cells. 1-Dodecanol, despite sharing the 12-carbon backbone and headgroup of farnesol, exhibited a significantly lower blocking affinity for N-type Ca2+ channels. Among several additional 12-carbon compounds tested, dodecylamine (DDA) mediated the highest affinity inhibition of N-type channels, indicating that the functional headgroup is a critical determinant of blocking affinity. This inhibition was concentration-dependent and relatively non-discriminatory among N-, L-, P/Q-, and R-Ca2+ channel subtypes. However, whereas L-type channels exhibited predominantly resting channel block, the non-L-type isoforms showed substantial rapid open channel block manifested by a speeding of the apparent time course of current decay and block of the inactivated state. Consistent with these findings, we observed significant frequency-dependence of block and dependence on external Ba2+ concentration for N-type, but not L-type, channels. We also systematically investigated the drug structural requirements for N-type channel inhibition. Blocking affinity varied with carbon chain length and showed a clear maximum at C12 and C13, with shorter and longer molecules producing progressively weaker peak current block. Overall, our data indicate that aliphatic monoamines may constitute a novel class of potent inhibitors of voltage-dependent Ca2+ channels, with block being governed by rigid structural requirements and channel-specific state dependencies
Veronica Davis Gerald on Gullah Culture
No full textVeronica Davis Gerald is Director of the Charles Joyner Institute for Gullah and African Diaspora Studies at Coastal Carolina University. In this video abstract, she discusses her identity as both a scholar and native of the Gullah culture. This informs her collaborative work with the Charles Joyner Institute and Gullah communities of the Waccamaw Neck region of South Carolina. Keywords: Gullah Culture, Charles Joyner Institute, South Carolina, GUL
Cloning, characterization, and modulation of voltage-gated calcium channels
No full textBibliography: p. 211-24
Molecular determinants of syntaxin 1A interactions with Cav2 calcium channels
No full textBibliography: p. 111-128Some pages are in colour
The functional effects of the neuronal rgk protein rem2
No full textBibliography: p. 162-175Many pages are in colour
GPCR and g-protein mediated regulation of cav2.2 calcium channels
No full textBibliography: p. 186-211Some pages are in colour
Cellular and Network Substrates of Neuronal Excitability in Relation to Epileptic Seizures
No full textBibliography: p. 166-208Brain function is, in part, maintained by an appropriate balance between excitatory and inhibitory elements. In relation to excitability, factors such as the complement and distribution of ion channels, properties and composition of synaptic proteins, and dynamics affecting network synchrony all interact to modulate neuronal firing and network activity. In this dissertation, I present a series of three focused studies at the level of ion channels (T-type calcium channels), synaptic transmission (prion protein), and network activity (high frequency oscillations) that affect neuronal excitability. With regards to Cav3.2 T-type voltage-gated calcium channels, I
demonstrate that novel missense mutations, as identified in patients with idiopathic generalized epilepsies, can result in alteration of channel biophysical properties. The majority of mutants altered gating properties consistent with greater channel activity. However, most of these biophysical alterations were not large in magnitude suggesting that the role of these channels in relation to other cellular processes may be affected. At the level of synapses, I describe a novel interaction/modulation of NMDA receptor currents by the endogenous prion protein (PrP). Using PrP-null mice, I show that loss of PrP results in enhanced synaptic NMDA currents with
greater amplitude and prolonged deactivation kinetics. These changes do not seem to be related to developmental effects and possibly involve an NMDA receptor subunit switch to functional receptors containing NR2D. At the network level, I show that high frequency oscillations in field recordings in vitro and in the EEG from patients with epilepsy are localized to the seizure onset zone and increase over time during the immediate pre-seizure period. This knowledge can be used to better localized seizures for surgical resection, thereby improving seizure control in intractable patients. These three topics and their relevance to hyperexcitable states are discussed in the context of epileptiform seizure activity and neurological disease
Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain
No full textT-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds
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