Pharmacology and Surface Electrostatics of the K Channel Outer Pore Vestibule

Abstract

Abstract. In spite of a generally well-conserved outer vestibule and pore structure, there is considerable diversity in the pharmacology of K channels. We have investigated the role of specific outer vestibule charged residues in the pharmacology of K channels using tetraethylammonium (TEA) and a trivalent TEA analog, gallamine. Similar to Shaker K channels, gallamine block of Kv3.1 channels was more sensitive to solution ionic strength than was TEA block, a result consistent with a contribution from an electrostatic potential near the blocking site. In contrast, TEA block of another type of K channel (Kv2.1) was insensitive to solution ionic strength and these channels were resistant to block by gallamine. Neutralizing either of two lysine residues in the outer vestibule of these Kv2.1 channels conferred ionic strength sensitivity to TEA block. Kv2.1 channels with both lysines neutralized were sensitive to block by gallamine, and the ionic strength dependence of this block was greater than that for TEA. These results demonstrate that Kv3.1 (like Shaker) channels contain negatively charged residues in the outer vestibule of the pore that influence quaternary ammonium pharmacology. The presence of specific lysine residues in wild-type Kv2.1 channels produces an outer vestibule with little or no net charge, with important consequences for quaternary ammonium block. Neutralizing these key lysines results in a negatively charged vestibule with pharmacological properties approaching those of other types of K channels.

Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA2-Type Toxin from Micrurus dumerilii carinicauda Coral Snake Venom

“…These proteins form heteromultimers with the so-called γ- or silent subunits of the Kv5, Kv6, Kv8, and Kv9 subfamilies [21]. DRG neurons express Kv2 α-subunits as well as several of Kv2 homotetramers and silencing Kv subunits (KvS) that heterotetramerize with Kv2 subunits [18], with the latter affecting Kv2 channel properties and pharmacology [22,23,24,25,26,27,28]. Since it is currently unknown which subunit combination of Kv2 delayed-rectifier channels is expressed in which DRG neuron type, it also remains to be determined which heteromultimeric Kv2 channel types represent the MiDCA1 target.…”

Nonspecific block of voltage-gated potassium channels has greater effect on distal schaffer collaterals than proximal schaffer collaterals during periods of high activity

“…Considering the K + channels known to be present within Schaffer collaterals, K V 1.2 is the most likely candidate for unique effects of 4-AP; K V 1.2 should have been minimally affected by the TEA concentration we used (Grissmer et al 1994;Al-Sabi et al 2013), but should have been partially blocked by the 4-AP concentration we used (Po et al 1993;Grissmer et al 1994). Unique effects of TEA could have been mediated by K V 1.1, K V 2, K V 7, or K Ca 1.1, all of which may be at least partially blocked by the TEA concentration we used (Frech et al 1989;St€ uhmer et al 1989;Lang andRitchie 1990, Taglialatela et al 1991;Po et al 1993;Grissmer et al 1994;Shieh and Kirsch 1994;Shen et al 1994;G omez-Hernandez et al 1997;Gutman et al 2005;Quinn and Begenisich 2006;Tang et al 2010;Al-Sabi et al 2013), but should be insensitive to the 4-AP concentration we used (Frech et al 1989;St€ uhmer et al 1989;Kirsch et al 1993;Grissmer et al 1994;Gutman et al 2005;Tang et al 2010). Our suggestion that block of K V 1.2 by 4-AP is responsible for enhanced depression of excitability may seem at odds with the conclusions of Palani et al (2010) that block of K V 1.2 causes hyperexcitability, but as discussed above, there are substantial differences in the stimulation pattern (high-frequency and burst stimulation vs. single and paired stimulation) and quantity (160 stimuli vs. 1 or 2 stimuli) between this study and Palani et al (2010).…”