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

Abstract

1. INTRODUCTION 358

1.1 Summary 358

1.2 Overview 359

1.3 Four classes of pore-forming K⁺channel subunits – necessary and (sometimes) sufficient 361

1.4 Soluble and peripheral membrane proteins that interact with P loop subunits to alter function 362

1.5 Integral membrane proteins that interact with P loop subunits to alter function 363

2. MinK DETERMINES THE FUNCTION OF MIXED CHANNEL COMPLEXES 363

2.1 The KCNE1 gene product (MinK) gives rise to K⁺-selective currents and controversy 363

2.2 MinK assembles with a P loop protein, KvLQT1, to form K⁺channels with unique function 364

2.2.1 Single-channel conductance of KvLQT1 and MinK/KvLQT1 channels 366

2.2.2 Other differences between KvLQT1 and MinK/KvLQT1 channels 367

2.3 MinK assembles with HERG, another P loop subunit, to regulate channel activity 368

2.4 MinK does not form chloride-selective ion channels 368

3. EXPERIMENTAL AND NATURAL MinK MUTATIONS 369

3.1 Site-directed mutations 369

3.1.1 MinK mutation alters basic channel attributes and identifies key residues 369

3.1.2 MinK is a Type I transmembrane peptide 370

3.1.3 MinK is intimately associated with the I_Kspore 370

3.1.4 The number of MinK subunits in I_Kschannel complexes 372

3.2 KCNE1 mutations associated with arrhythmia and deafness alter I_Kschannel function 373

3.3 Summary of MinK sites critical to I_Kschannel function 374

4. MinK-RELATED PEPTIDES: AN EMERGING SUPERFAMILY 374

4.1 KCNE2, 3 and 4 encode MinK-related peptides 1, 2 and 3 (MiRPs) 374

4.2 MiRP1 assembles with a P loop protein, HERG, to form K⁺channels with unique function 375

4.2.1 MiRP1 alters activation, deactivation and single-channel conductance 376

4.2.2 MiRP1 alters regulation by K⁺ion and confers biphasic kinetics to channel blockade 378

4.2.3 Stable association of MiRP1 and HERG subunits 380

4.3 KCNE2 mutations are associated with arrhythmia and decreased K⁺flux 383

4.4 Summary of the evidence that cardiac I_Krchannels are MiRP1/HERG complexes 385

5. MinK-RELATED PEPTIDES: COMMONALTIES AND IMPLICATIONS 386

5.1 Genetics and structure 386

5.2 Cell biology and function 387

6. ANSWERS, SOME OUTSTANDING ISSUES, CONCLUSIONS 387

7. ACKNOWLEDGEMENTS 389

8. REFERENCES 389

MinK 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 I_Ks and I_Kr, 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.