A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs).

1. INTRODUCTION 3581.1 Summary 3581.2 Overview 3591.3 Four classes of pore-forming K+ channel subunits – necessary and (sometimes) sufficient 3611.4 Soluble and peripheral membrane proteins that interact with P loop subunits to alter function 3621.5 Integral membrane proteins that interact with P loop subunits to alter function 3632. MinK DETERMINES THE FUNCTION OF MIXED CHANNEL COMPLEXES 3632.1 The KCNE1 gene product (MinK) gives rise to K+-selective currents and controversy 3632.2 MinK assembles with a P loop protein, KvLQT1, to form K+ channels with unique function 3642.2.1 Single-channel conductance of KvLQT1 and MinK/KvLQT1 channels 3662.2.2 Other differences between KvLQT1 and MinK/KvLQT1 channels 3672.3 MinK assembles with HERG, another P loop subunit, to regulate channel activity 3682.4 MinK does not form chloride-selective ion channels 3683. EXPERIMENTAL AND NATURAL MinK MUTATIONS 3693.1 Site-directed mutations 3693.1.1 MinK mutation alters basic channel attributes and identifies key residues 3693.1.2 MinK is a Type I transmembrane peptide 3703.1.3 MinK is intimately associated with the IKs pore 3703.1.4 The number of MinK subunits in IKs channel complexes 3723.2 KCNE1 mutations associated with arrhythmia and deafness alter IKs channel function 3733.3 Summary of MinK sites critical to IKs channel function 3744. MinK-RELATED PEPTIDES: AN EMERGING SUPERFAMILY 3744.1 KCNE2, 3 and 4 encode MinK-related peptides 1, 2 and 3 (MiRPs) 3744.2 MiRP1 assembles with a P loop protein, HERG, to form K+ channels with unique function 3754.2.1 MiRP1 alters activation, deactivation and single-channel conductance 3764.2.2 MiRP1 alters regulation by K+ ion and confers biphasic kinetics to channel blockade 3784.2.3 Stable association of MiRP1 and HERG subunits 3804.3 KCNE2 mutations are associated with arrhythmia and decreased K+ flux 3834.4 Summary of the evidence that cardiac IKr channels are MiRP1/HERG complexes 3855. MinK-RELATED PEPTIDES: COMMONALTIES AND IMPLICATIONS 3865.1 Genetics and structure 3865.2 Cell biology and function 3876. ANSWERS, SOME OUTSTANDING ISSUES, CONCLUSIONS 3877. ACKNOWLEDGEMENTS 3898. REFERENCES 389MinK and MinK-related peptide 1 (MiRP1) are integral membrane peptides with a single transmembrane span. These peptides are active only when co-assembled with pore-forming K+ channel subunits and yet their role in normal ion channel behaviour is obligatory. In the resultant complex the peptides establish key functional attributes: gating kinetics, single-channel conductance, ion selectivity, regulation and pharmacology. Co-assembly is required to reconstitute channel behaviours like those observed in native cells. Thus, MinK/KvLQT1 and MiRP1/HERG complexes reproduce the cardiac currents called IKs and IKr, respectively. Inherited mutations in KCNE1 (encoding MinK) and KCNE2 (encoding MiRP1) are associated with lethal cardiac arrhythmias. How these mutations change ion channel behaviour has shed light on peptide structure and function. Recently, KCNE3 and KCNE4 were isolated. In this review, we consider what is known and what remains controversial about this emerging superfamily.