Subunit Composition of Kv1 Channels in Human CNS

The α subunits of Shaker-related K+ channels (Kv1.X) show characteristic distributions in mammalian brain and restricted coassembly. Despite the functional importance of these voltage-sensitive K+ channels and involvement in a number of diseases, little progress has been achieved in deciphering the subunit composition of the (α)4(β)4 oligomers occurring in human CNS. Thus, the association of α and β subunits was investigated in cerebral grey and white matter and spinal cord from autopsy samples. Immunoblotting established the presence of Kv1.1, 1.2, and 1.4 in all the tissues, with varying abundance. Sequential immunoprecipitations identified the subunits coassembled. A putative tetramer of Kv1.3/1.4/1.1/1.2 was found in grey matter. Both cerebral white matter and spinal cord contained the heterooligomers Kv1.1/1.4 and Kv1.1/1.2, similar to grey matter, but both lacked Kv1.3 and the Kv1.4/1.2 combination. An apparent Kv1.4 homooligomer was detected in all the samples, whereas only the brain tissue possessed a putative Kv1.2 homomer. In grey matter, Kvβ2.1 was coassociated with the Kv1.1/1.2 combination and Kv1.2 homooligomer. In white matter, Kvβ2.1 was associated with Kv1.2 only, whereas Kvβ1.1 coprecipitated with all the α subunits present. This represents the first description of Kv1 subunit complexes in the human CNS and demonstrates regional variations, indicative of functional specialisation

Exploitation of botulinum neurotoxins for research and clinical purposes

SIGLEAvailable from British Library Document Supply Centre- DSC:0678.231F(AD-A--294284)(microfiche) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Homologues of a K+ channel blocker α-dendrotoxin: characterization of synaptosomal binding sites and their coupling to elevation of cytosolic free calcium concentration

International audienceThree polypeptides (β, γ and δ) homologous to α-dendrotoxin, an inhibitor of certain voltage-activated K+ channels, were found to elevate the cytosolic free concentration of calcium ([Ca2+]c) in isolated central nerve terminals. Relative to α-dendrotoxin (EC50 − 2.1 nM), the β-, γ- and δ-toxins were 790-, 214- and 5.7-fold less effective; no additivity was apparent in the toxins' effects on [Ca2+]c. Each toxin antagonized the high affinity binding of 125I-labelled α- and δ-dendrotoxin to synaptosomes but with different potencies. The mutual interaction of α- and δ-dendrotoxin with the acceptor appeared complex, the inhibition curves being noticeably extended. For the inhibition of binding of α- and δ-dendrotoxin, the respective Ki's (nM) observed for α, β, γ and δ toxins were 0.78, 50, 99, 8, and 2.3, 95, 61, 0.53. Apparently, interactions of α- and δ-, but not β- or γ-dendrotoxin with the acceptor are closely coupled to an inhibition of K+ channel(s) as observed indirectly by elevation of [Ca2+]c

Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhi

Protease inhibitor homologues of dendrotoxin do not bind to dendrotoxin acceptors on synaptosomal membranes or facilitate neuromuscular transmission

The dendrotoxins are a homologous group of potassium channel-blocking polypeptides found in mamba snake venom. They are similar in sequence and structure to Kunitz-type serine protease inhibitors. Modified and native protease inhibitors were assayed for dendrotoxin-like activity using radioligand-binding and twitch tension-recording methods. Despite the large number and high concentration of compounds tested, no protease inhibitor displayed dendrotoxin-like activity. The results indicate that the protease-inhibiting and potassium channel-blocking activities of these two groups of polypeptides are not linked