Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: A transmembrane beta-subunit homolog

Voltage-dependent and calcium sensitive K+ (MaxiK) channels are key regulat ors of neuronal excitability, secretion, and vascular tone because of their ability to sense transmembrane voltage and intracellular Ca2+. In most tis sues, their stimulation results in a noninactivating hyperpolarizing K+ cur rent that reduces excitability, In addition to noninactivating MaxiK curren ts, an inactivating MaxiK channel phenotype is found in cells like chromaff in cells and hippocampal neurons, The molecular determinants underlying ina ctivating MaxiK channels remain unknown. Herein, we report a transmembrane beta subunit (beta 2) that yields inactivating MaxiK currents on coexpressi on with the pore-forming alpha subunit of MaxiK channels. Intracellular app lication of trypsin as well as deletion of 19 N-terminal amino acids of the beta 2 subunit abolished inactivation of the alpha subunit. Conversely, fu sion of these N-terminal amino acids to the noninactivating smooth muscle b eta 1 subunit leads to an inactivating phenotype of MaxiK channels. Further more, addition of a synthetic N-terminal peptide of the beta 2 subunit caus es inactivation of the MaxiK channel alpha subunit by occluding its K+-cond ucting pore resembling the inactivation caused by the "ball" peptide in vol tage-dependent K+ channels. Thus, the inactivating phenotype of MaxiK chann els in native tissues can result from the association with different beta s ubunits.