Spermine Is Fit to Block Inward Rectifier (Kir) Channels

Molecular biology has shown there to be a great diversity of potassium channel isoforms. Among the simplest structurally are the inward rectifier potassium channel, KCNJ gene family. These channels are open in the region of the resting potential, a potential that they therefore help to determine. Some 14 genes are known for this family, classified into 7 subfamilies in terms of sequence homology or identity. These subfamilies are identified as Kir1.0 through Kir7.0 (for review see Stan-field et al., 2002). Inward rectifier channels are tetramers of pore-forming subunits with two transmembrane domains (M1 and M2) separated by a P-region that forms the most selective part of the pore (Fig. 1). Significantly more than half the molecular mass is made up by the intra-cellular NH 2 and particularly the COOH terminus. The X-ray structure of a bacterial homologue (KirBac1.1) shows that the NH 2 and the COOH terminus form an extension of the pore beyond the inner surface of the membrane into the cytoplasm (Kuo et al., 2003). This extension roughly doubles the pore length. This structure holds for mammalian channels as well (Nishida and MacKinnon, 2002). Additional subunits are required for some members of the family to make chan-nels—e.g., K ATP is formed from Kir6.2 and the sulpho-nylurea receptor SUR. But the majority appear not to require accessory subunits. Why are these potassium channels called inward recti-fiers? When Katz first discovered the phenomenon of inward rectification (Katz, 1949), he showed in skeletal muscle that if the extracellular solution contained a high [K ϩ ], hyperpolarization gave rise to a high K ϩ perme-ability, while depolarization gave rise to a low permeabil-ity. Thus, K ϩ moved into the cell more easily than it moved out. This behavior was entirely unexpected, particularly so at a time when the mechanism of the nervous impulse was being elucidated, where K ϩ permeability in nerve increased with depolarization. The behavior was later shown to be a characteristic of the resting potassium conductance of skeletal muscle whatever the initial level [K ϩ ] o (Hodgkin and Horowicz, 1959; Leech and Stanfield, 1981). Thus, even at physiological [K ϩ ] o , K ϩ moves in more easily under hyperpolarization than it moves out. Two factors, then, regulate the K ϩ permeabil-ity underlying inward rectification. It is increased at more negative membrane potentials. And, at a given membrane potential, it is increased with increasing [K ϩ ] …