Emerging issues of connexin channels: biophysics fills the gap

Abstract

1. Introduction 3261.1 What? Terminology and general properties 3271.2 Why? Reasons for biophysical study 3291.3 How? Special issues for study of connexin channels 3302. Molecular and structural context 3312.1 Biochemical features 3312.2 Structures 3342.2.1 Junctional channels 3352.2.2 Hemichannels 3382.2.3 Heteromeric channels 3422.2.4 Junctional plaques 3473. Experimental approaches and issues specific to study of connexin channel physiology 3493.1 Macroscopic currents 3493.1.1 Junctional channels 3493.1.2 Hemichannels 3543.2 Single-channel currents 3553.2.1 Junctional channels 3553.2.2 Hemichannels 3583.3 Molecular permeability 3613.3.1 A selection of tracers 3613.3.2 Junctional channels 3623.3.3 Hemichannels 3663.4 Other 3674. Structural issues 3684.1 What lines the pore? 3684.2 Docking between hemichannels 3734.2.1 Structural and molecular basis 3744.2.2 Determinants of specificity of interaction 3805. Permeability and selectivity 3815.1 Among the usual ions 3835.1.1 Unitary conductance 3835.1.2 Selectivity 3845.1.3 Nonlinear single-channel I–V relations and their molecular determinants 3865.2 Among large permeants 3915.2.1 Uncharged molecules 3925.2.2 Charged molecules 3935.2.3 Cytoplasmic/signaling molecules 3966. Voltage sensitivity 3996.1 Macroscopic transjunctional voltage sensitivity 4046.2 Microscopic voltage sensitivity – Vj-gating 4076.2.1 Molecular basis – voltage sensor 4076.2.2 Molecular basis – transduction and/or state stability 4096.3 Microscopic voltage sensitivity – loop gating 4126.4 Vm-gating 4147. Direct chemical modulation 4157.1 Phosphorylation 4177.2 Cytoplasmic pH and aminosulfonates 4197.3 Calcium ion 4247.4 Lipophiles 4247.4.1 Long chain n-alkyl alcohols 4257.4.2 Fatty acids and fatty acid amides 4267.4.3 Halothane 4267.5 Glycyrrhetinic acid and derivatives 4277.6 Cyclic nucleotides 4287.7 Other candidates 4308. Connexinopathies 4319. Summary 43510. Acknowledgements 43811. References 438Connexins are the proteins that form the intercellular channels that compose gap junctions in vertebrates. Connexin channels mediate electrotonic coupling between cells and serve important functions as mediators of intercellular molecular signaling. Convincing demonstration of the latter function has been elusive, as have the experimental tools required for detailed functional study of the channels. Recently, substantial progress has been made on both fronts. Connexin channels are now known to be dynamic, multifunctional channels intimately involved in development, physiology and pathology, and amenable to study by state-of-the-art approaches. A host of developmental and physiological defects are caused by defects in connexin channels, and therefore in the intercellular molecular movement they mediate. The channel structure has been determined to 7·5 Å resolution within the plane of the membrane. Experimental paradigms have been developed that enable application of the tools of modern channel biophysics to study connexin channel structure–function. As a result, the biophysical mechanisms and biological functions of connexin channels now enjoy a vigorous and expanding experimental interest. This article focuses on the former, but with attention to issues likely to have biological consequences.