Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion...Continue Reading
SNX-111, a novel, presynaptic N-type calcium channel antagonist, is neuroprotective against focal cerebral ischemia in rabbits
Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation
Biophysical properties, pharmacology, and modulation of human, neuronal L-type (alpha(1D), Ca(V)1.3) voltage-dependent calcium currents
Evidence for two concentration-dependent processes for beta-subunit effects on alpha1B calcium channels
Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes
Overexpressed Ca(v)beta3 inhibits N-type (Cav2.2) calcium channel currents through a hyperpolarizing shift of ultra-slow and closed-state inactivation
Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain
Alternative splicing in the voltage-sensing region of N-Type CaV2.2 channels modulates channel kinetics
Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells
The psychological behaviorism theory of pain and the placebo: its principles and results of research application
Hot regions in protein--protein interactions: the organization and contribution of structurally conserved hot spot residues
The importance of occupancy rather than affinity of CaV(beta) subunits for the calcium channel I-II linker in relation to calcium channel function
Kinetics of internalization and degradation of N-type voltage-gated calcium channels: role of the alpha2/delta subunit
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors
Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaValpha1 AID-CaVbeta interaction site that is critical for channel modulation
Time course and specificity of the pharmacological disruption of the trafficking of voltage-gated calcium channels by gabapentin
The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin
Targeting multiple conformations leads to small molecule inhibitors of the uPAR·uPA protein-protein interaction that block cancer cell invasion
Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface
The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment
Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions
Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes.
The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential
Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor
Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential
Molecular Determinants of the Sensitivity to Gq/11-Phospholipase C-dependent Gating, Gd3+ Potentiation, and Ca2+ Permeability in the Transient Receptor Potential Canonical Type 5 (TRPC5) Channel.
A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary CaV β subunits
Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel.
Caveolins & Signal Transduction
Caveolins are small proteins with a hairpin loop conformation that are located in the plasma membrane of various cell types where they bind cholesterol and interact with receptors essential for several signal transduction pathways. Here is the latest research.