The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

/pdf/the-glutamate-receptor-ion-channels-560mntczdb.pdf

The glutamate receptor ion channels

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/411.full.pdf

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through L...

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

/pdf/voltage-gated-calcium-channels-1bodtqjbcd.pdf

Voltage-Gated Calcium Channels

Voltage-gated sodium (NaV) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na+ channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 A resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4–S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ∼4.6 A wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na+ selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level. The X-ray crystal structure of a voltage-gated sodium channel from Arcobacter butzleri has been determined, with the channel in the closed-pore conformation. Channels of this type initiate electrical signalling in excitable cells and are the molecular targets for many drugs, but the structural basis for their voltage-dependent activation and ion selectivity is not known. The selectivity filter in this sodium channel is found to be quite short, compared with those in open-pore potassium channels, and the voltage-sensor domains and linkers between segments S4 and S5 seem to dilate the central pore by pivoting together.

The crystal structure of a voltage-gated sodium channel

We describe the first potent and selective blocker of the class E Ca2+channel. SNX-482, a novel 41 amino acid peptide present in the venom of the African tarantula, Hysterocrates gigas, was identif...

Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas.

Hydrogen ions are important regulators of ion flux through voltage-gated Ca2+ channels but their site of action has been controversial. To identify molecular determinants of proton block of L-type Ca2+ channels, we combined site-directed mutagenesis and unitary current recordings from wild-type (WT) and mutant L-type Ca2+ channels expressed in Xenopus oocytes. WT channels in 150 mM K+ displayed two conductance states, deprotonated (140 pS) and protonated (45 pS), as found previously in native L-type Ca2+ channels. Proton block was altered in a unique fashion by mutation of each of the four P-region glutamates (EI-EIV) that form the locus of high affinity Ca2+ interaction. Glu(E)-->Gln(Q) substitution in either repeats I or III abolished the high-conductance state, as if the titration site had become permanently protonated. While the EIQ mutant displayed only an approximately 40 pS conductance, the EIIIQ mutant showed the approximately 40 pS conductance plus additional pH-sensitive transitions to an even lower conductance level. The EIVQ mutant exhibited the same deprotonated and protonated conductance states as WT, but with an accelerated rate of deprotonation. The EIIQ mutant was unusual in exhibiting three conductance states (approximately 145, 102, 50 pS, respectively). Occupancy of the low conductance state increased with external acidification, albeit much higher proton concentration was required than for WT. In contrast, the equilibrium between medium and high conductance levels was apparently pH-insensitive. We concluded that the protonation site in L-type Ca2+ channels lies within the pore and is formed by a combination of conserved P-region glutamates in repeats I, II, and III, acting in concert. EIV lies to the cytoplasmic side of the site but exerts an additional stabilizing influence on protonation, most likely via electrostatic interaction. These findings are likely to hold for all voltage-gated Ca2+ channels and provide a simple molecular explanation for the modulatory effect of H+ ions on open channel flux and the competition between H+ ions and permeant divalent cations. The characteristics of H+ interactions advanced our picture of the functional interplay between P-region glutamates, with important implications for the mechanism of Ca2+ selectivity and permeation.

https://rupress.org/jgp/article-pdf/108/5/363/1214652/363.pdf

Molecular basis of proton block of L-type Ca2+ channels.

Among voltage-gated Ca2+ channels the non-dihydropyridine-sensitive alpha1E subunit is functionally less well characterized than the structurally related alpha1A (omega-agatoxin-IVA sensitive, P- /Q-type) and alpha1B (omega-conotoxin-GVIA sensitive, N-type) subunits. In the rat insulinoma cell line, INS-1, a tissue-specific splice variant of alpha1E (alpha1Ee) has been characterized at the mRNA and protein levels, suggesting that INS-1 cells are a suitable model for investigating the function of alpha1Ee. In alpha1E-transfected human embryonic kidney (HEK-293) cells the alpha1E-selective peptide antagonist SNX-482 (100 nM) reduces alpha1Ed- and alpha1Ee-induced Ba2+ inward currents in the absence and presence of the auxiliary subunits beta3 and alpha2delta-2 by more than 80%. The inhibition is fast and only partially reversible. No effect of SNX-482 was detected on the recombinant T-type Ca2+ channel subunits alpha1G, alpha1H, and alpha1I showing that the toxin from the venom of Hysterocrates gigas is useful as an alpha1E-selective antagonist. After blocking known components of Ca2+ channel inward current in INS-1 cells by 2 microM (+/-)-isradipine plus 0.5 microM omega-conotoxin-MVIIC, the remaining current is reduced by 100 nM SNX-482 from -12.4 +/- 1.2 pA/pF to -7.6 +/- 0.5 pA/pF (n = 9). Furthermore, in INS-1 cells, glucose- and KCl-induced insulin release are reduced by SNX-482 in a dose-dependent manner leading to the conclusion that alpha1E, in addition to L-type and non-L-type (alpha1A-mediated) Ca2+ currents, is involved in Ca2+ dependent insulin secretion of INS-1 cells.

Functional coupling between ‘R-type’ Ca2+ channels and insulin secretion in the insulinoma cell line INS-1

Aspartate Substitutions Establish the Concerted Action of P-region Glutamates in Repeats I and III in Forming the Protonation Site of L-type Ca2+ Channels

The prospect of rewards can have strong modulatory effects on response preparation. Importantly, selection and execution of movements in real life happens under an environment characterized by uncertainty and dynamic changes. The current study investigated how the brain9s motor system adapts to the dynamic changes in the environment in pursuit of rewards. In addition, we studied how the prefrontal cognitive control system contributes in this adaptive control of motor behavior. To this end, we tested the effect of rewards and expectancy on the hallmark neural signals that reflect activity in motor and prefrontal systems, the lateralized readiness potential (LRP) and the mediofrontal (mPFC) theta oscillations, while participants performed an expected and unexpected action to retrieve rewards. To better capture the dynamic changes in neural processes represented in the LRP waveform, we decomposed the LRP into the preparation (LRPprep) and execution (LRPexec) components. The overall pattern of LRPprep and LRPexec confirmed that they each reflect motor preparation based on the expectancy and motor execution when making a response that is either or not in line with the expectations. In the comparison of LRP magnitude across task conditions, we found a greater LRPprep when large rewards were more likely, reflecting a greater motor preparation to obtain larger rewards. We also found a greater LRPexec when large rewards were presented unexpectedly, suggesting a greater motor effort placed for executing a correct movement when presented with large rewards. In the analysis of mPFC theta, we found a greater theta power prior to performing an unexpected than expected response, indicating its contribution in response conflict resolution. Collectively, these results demonstrate an optimized motor control to maximize rewards under the dynamic changes of real-life environment.

/pdf/reward-and-expectancy-effects-on-neural-signals-of-motor-45pwp9wbyd.pdf

Xiao-hua Chen

Papers

Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas.

Molecular basis of proton block of L-type Ca2+ channels.

Functional coupling between ‘R-type’ Ca2+ channels and insulin secretion in the insulinoma cell line INS-1

Aspartate Substitutions Establish the Concerted Action of P-region Glutamates in Repeats I and III in Forming the Protonation Site of L-type Ca2+ Channels

Reward and expectancy effects on neural signals of motor preparation and execution