ABSTRACT
Contents 20.1 Introduction 276 20.2 Gene identication 276 20.3 Biophysical, pharmacological, and structural features 277
20.3.1 Overview 277 20.3.2 Determinants of KCNQ channel assembly 277 20.3.3 Pharmacology 278 20.3.4 Receptors and signal transduction 279 20.3.5 Regulation of KCNQ channels by PIP2 279 20.3.6 Lipid specicity and location of the PIP2-binding site 281 20.3.7 Receptor specicity 281
20.4 Auxiliary subunits and regulatory proteins of KCNQ channels 282 20.4.1 Calmodulin in KCNQ channel function 282 20.4.2 A-kinase anchoring protein (AKAP) 79/150 and PKC action 283 20.4.3 Regulation of KCNQ channels by KCNE subunits 283
20.4.3.1 KCNQ1/KCNE1 283 20.4.3.2 Other KCNE subunits 285 20.4.3.3 Eects of KCNEs on KCNQ channel tracking 286
20.4.4 Other molecular partners of KCNQ channels 286 20.5 M-channel expression and function in mammalian tissues 286
20.5.1 Function of KCNQ channels in the peripheral nervous system 286 20.5.1.1 Sympathetic system 286 20.5.1.2 Peripheral somatosensory system 286
20.5.2 Functions of KCNQ channels in the central nervous system 287 20.5.2.1 KCNQ2/3 287 20.5.2.2 KCNQ4 289 20.5.2.3 KCNQ5 289 20.5.2.4 KCNQ1 289
20.5.3 Heart 289 20.5.4 Other tissues 289
20.5.4.1 Epithelia 289 20.5.4.2 Smooth and skeletal muscles 290 20.5.4.3 Other tissues/structures 290
20.6 M-channelopathies and therapeutic potential of KCNQ channels 290 20.6.1 Arrhythmias 290
20.6.1.1 Long QT syndrome 290 20.6.1.2 Short QT syndrome 291
20.6.2 Deafness 291 20.6.3 Epilepsy/seizures 291 20.6.4 Pain 292 20.6.5 M-channels as drug targets 292
20.1 INTRODUCTION As for most of the ion channels discussed in this volume, the currents carried by KCNQ K+ channels were characterized by pharmacological, kinetic, or functional features long before their gene identication, and so have established names reecting those features. In the central nervous system (CNS) and the peripheral nervous system (PNS) neurons, this corresponds to the M-current, rst described by David Brown and colleagues in sympathetic ganglia as a voltage-gated, noninactivating K+ current depressed by the stimulation of muscarinic acetylcholine receptors (mAChRs) (1,2). ese investigators were searching for the molecular basis of the slow excitatory postsynaptic potential (EPSP), the prolonged depolarization occurring with a delay after a synaptic EPSP seen after trains of action potentials (3). e slow EPSP proved to be due to the closure of the M-type K+ current via mAChR stimulation and actions of Gq/11 G proteins, an eect also mediated by a variety of peptide neurotransmitters, such as Gonadotropin-releasing hormone (GnRH) (Luteinizinghormone-releasing hormone (LHRH) in frog), substance P, angiotensin II, and others (4). e inhibition of M-current (IM) generally increases excitability as the standing K+ conductance at resting potentials is reduced (Figure 20.1). IM is well poised to serve this role due to its lack of inactivation, threshold for activation near neuronal resting potentials, and slow kinetics (5). In the heart, a similar K+ current with even slower kinetics, dubbed IKs, underlies much of the initial repolarization after the cardiac action potential and is sensitive to protein kinase A (PKA), making it partly responsible for the speeding of the heart rate upon adrenergic stimulation (6). Neither IM nor IKs is particularly sensitive to the well-known blocker of most delayed rectiers, tetraethylammonium (TEA) ions or various scorpion
toxins. Much study has been spent answering two fundamental questions for these K+ currents: the molecular correlates underlying them and the signal transduction mechanisms linking muscarinic or β-adrenergic stimulation to modulation of M-current, or IKs, respectively. As we see in the following, the major clues for both questions came from inherited diseases in people linked to specic gene loci.
