T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures.

Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels.

Characterization of the substituted N-triazole oxindole TROX-1, a small-molecule, state-dependent inhibitor of Ca(V)2 calcium channels.

Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca(V)2.2) as therapeutic targets for chronic pain. A state-dependent Ca(V)2.

A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain.

Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.

Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker.

Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.

A fluorescence-based high-throughput screening assay for the identification of T-type calcium channel blockers.

T-type voltage-gated Ca(2+) channels have been implicated in contributing to a broad variety of human disorders, including pain, epilepsy, sleep disturbances, cardiac arrhythmias, and certain types of cancer. However, potent and selective T-type Ca(2+) channel modulators are not yet available for clinical use. This may in part be due to their unique biophysical properties that have delayed the development of high-throughput screening (HTS) assays for identifying blockers.

SCAM analysis reveals a discrete region of the pore turret that modulates slow inactivation in Kv1.5.

In Kv1.5, protonation of histidine 463 in the S5-P linker (turret) increases the rate of depolarization-induced inactivation and decreases the peak current amplitude. In this study, we examined how amino acid substitutions that altered the physico-chemical properties of the side chain at position 463 affected slow inactivation and then used the substituted cysteine accessibility method (SCAM) to probe the turret region (E456-P468) to determine whether residue 463 was unique in its ability to modulate the macroscopic current.

Synergistic inhibition of the maximum conductance of Kv1.5 channels by extracellular K+ reduction and acidification.

Voltage-gated potassium (Kv) channels exist in the membranes of all living cells. Of the functional classes of Kv channels, the Kv1 channels are the largest and the best studied and are known to play essential roles in excitable cell function, providing an essential counterpoint to the various inward currents that trigger excitability. The serum potassium concentration [K(+)(o)] is tightly regulated in mammals and disturbances can cause significant functional alterations in the electrical behavior of excitable tissues in the nervous system and the heart.

Constitutive inactivation of the hKv1.5 mutant channel, H463G, in K+-free solutions at physiological pH.

Extracellular acidification and reduction of extracellular K(+) are known to decrease the currents of some voltage-gated potassium channels. Although the macroscopic conductance of WT hKv1.5 channels is not very sensitive to [K(+)](o) at pH 7.

The external K+ concentration and mutations in the outer pore mouth affect the inhibition of kv1.5 current by Ni2+.

By examining the consequences both of changes of [K+]o and of point mutations in the outer pore mouth, our goal was to determine if the mechanism of the block of Kv1.5 ionic currents by external Ni2+ is similar to that for proton block. Ni2+ block is inhibited by increasing [K+]o, by mutating a histidine residue in the pore turret (H463Q) or by mutating a residue near the pore mouth (R487V) that is the homolog of Shaker T449.

Molecular determinants of the inhibition of human Kv1.5 potassium currents by external protons and Zn(2+).

Using human Kv1.5 channels expressed in HEK293 cells we assessed the ability of H+o to mimic the previously reported action of Zn(2+) to inhibit macroscopic hKv1.5 currents, and using site-directed mutagenesis, we addressed the mechanistic basis for the inhibitory effects of H(+)(o) and Zn(2+).