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The “Sweet” Side of Ion Channels

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The “Sweet” Side of Ion Channels Rev Physiol Biochem Pharmacol (2014) 167: 67–114 DOI: 10.1007/112_2014_20 © Springer-Verlag Berlin Heidelberg 2014 Published online: 20 September 2014 The “Sweet” Side of Ion Channels Joanna Lazniewska and Norbert Weiss Abstract Ion channels play a crucial role in cell functioning, contributing to transmembrane potential and participating in cell signalling and homeostasis. To fulfil highly specialised functions, cells have developed various mechanisms to regulate channel expression and activity at particular subcellular loci, and alteration of ion channel regulation can lead to serious disorders. Glycosylation, one of the most common forms of co- and post-translational protein modification, is rapidly emerging as a fundamental mechanism not only controlling the proper folding of nascent channels but also their subcellular localisation, gating and function. More- over, studies on various channel subtypes have revealed that glycosylation repre- sents an important determinant by which other signalling pathways modulate channel activity. The discovery of detailed mechanisms of regulation of ion chan- nels by glycosylation provides new insights in the physiology of ion channels and may allow developing new pharmaceutics for the treatment of ion channel-related disorders. Keywords Ion channel • N-linked glycosylation • O-linked glycosylation • Glycan • Protein glycosylation Contents 1 Introduction ................................................................................... 69 2 Protein Glycosylation in a Nutshell .......................................................... 70 3 Means to Investigate Glycosylation of Ion Channels ....................................... 72 3.1 Identification of N-Linked Glycosylation .................................................72 3.2 Identification of O-Linked Glycosylation .................................................73 4 Glycosylation-Dependent Regulation of Ion Channels ... .................................. 73 J. Lazniewska and N. Weiss (*) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic e-mail: [email protected] [email protected] 68 J. Lazniewska and N. Weiss 4.1 Voltage-Gated Potassium Channels (Kv)........................................... 73 4.2 Voltage-Gated Sodium Channels (Nav)............................................. 80 4.3 Voltage-Gated Calcium Channels (Cav)............................................ 82 4.4 Hyperpolarisation-Activated Cyclic Nucleotide-Gated Channels (HCN) . 83 4.5 Transient Receptor Potential Channels (TRPs) ..................................... 84 4.6 Acid-Sensing Ion Channels (ASICs) ................................................ 88 4.7 Two-Pore Domain K+ Channels (TASK) ........................................... 89 4.8 Two-Pore Channels (TPCs) ......................................................... 90 4.9 Pannexin Channels (Panx) ........................................................... 91 4.10 CFTR Channel ....................................................................... 92 4.11 CLC Channels ........................................................................ 93 5 Crosstalk Between Glycosylation and Other Signalling Pathways ........................ 93 5.1 Regulation by Auxiliary Subunits .........................................................93 5.2 Klotho-Dependent Regulation of TRPV5 .................................................97 5.3 SP1 Induces CLC-2 Gene Expression .....................................................97 6 Modulation of Ion Channel Glycosylation by External Factors ........................... 97 6.1 Modulation by External Sugar .............................................................97 6.2 Modulation by Temperature ...............................................................98 7 Glycosylation-Mediated Channelopathy ................................................... 99 7.1 Long QT Syndrome ........................................................................99 7.2 Diabetic Neuropathic Pain .................................................................100 7.3 Cystic Fibrosis .............................................................................100 7.4 Varitint–Waddler Phenotype ..............................................................101 Conclusion and Perspectives .................................................................... 101 References ....................................................................................... 103 Abbreviations ASIC Acid-sensing ion channel B35 Neuroblastoma cell CAD Cath.a-differentiated cell Cav Voltage-gated calcium channel CDG Congenital disorders of glycosylation CFTR Cystic fibrosis transmembrane conductance regulator CHO Chinese hamster ovary cell ER Endoplasmic reticulum ERGIC ER–Golgi intermediate compartment GalNAc N-acetylgalactosamine GlcNAc-1-P N-acetylglucosamine-1-phosphate HCN Hyperpolarisation-activated cyclic nucleotide-gated channel K2P Two-pore domain potassium channel Kv Voltage-gated potassium channel LacNAc N-acetyllactosamine LQT Long QT syndrome M1 Murine cortical collecting duct Nav Voltage-gated sodium channel O-GalNAc Mucin-type O-glycan [email protected] The “Sweet” Side of Ion Channels 69 Panx Pannexin channel PNGase F Peptide-N-glycosidase F Sf9 Spodoptera frugiperda cell SKBR3 Human breast cancer cell ST3Gal4 Beta-galactoside alpha-2,3-sialyltransferase 4 ST8sia2 Alpha-2,8-sialyltransferase 2 TPC Two-pore channel TRIP8b Tetratricopeptide repeat-containing Rab8b-interacting protein TRP Transient receptor potential channel TRPC Transient receptor potential canonical channel TRPM Transient receptor potential melastatin channel TRPP Transient receptor potential polycystin channel TRPV Transient receptor potential vanilloid channel α-benzyl- 1-Benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside GalNAc 1 Introduction Ion channels are pore-forming integral membrane proteins whose main function is controlling the flow of ions across cell membranes. They are multimeric protein complexes expressed both in the plasma membrane and intracellular organelles and are key contributors to the cell “well-being” (Hille 2001). It is well established that ion channels undergo chemical and post-translational modifications including acet- ylation (Shipston 2014), phosphorylation (Davis et al. 2001) (Ismailov and Benos 1995) (Levitan 1994), methylation (Baek et al. 2014) (Palmieri et al. 2012), ubiquitination (Altier et al. 2011) (Abriel and Staub 2005) (Kantamneni et al. 2011) (Marangoudakis et al. 2012) (Waithe et al. 2011), SUMOylation (Rougier et al. 2010) (Rajan et al. 2005) (Dai et al. 2009) or palmitoylation (Shipston 2011), a fundamental process controlling their expression, activity and cellular function. Recently, protein glycosylation, a process commonly known to contribute to the endoplasmic reticulum (ER) quality control of nascent polypeptide chains and critical for the proper folding, sorting and trafficking of proteins that enter the secretory pathway (Weerapana and Imperiali 2006) (Roth et al. 2010) (Moremen et al. 2012), has been also shown to play a fundamental role in modu- lating ion channel function (Ednie and Bennett 2012). Using site-directed muta- genesis of glycosylation loci, pharmacological inhibition of protein glycosylation and enzymatic removal of glycans, it was shown that preventing protein glycosyl- ation drastically alters life cycle of ion channels (Gong et al. 2002) (Mant et al. 2013) (Weiss et al. 2013) and most importantly their intrinsic activity (Jing et al. 2012) (Pertusa et al. 2012). Moreover, glycosylation at specific channel loci appears to produce variable effects on a given channel, contributing to fine-tune channel activity and fulfil highly specialised cellular functions. Interestingly enough, glycosylation of ion channels also represents a fundamental regulatory [email protected] 70 J. Lazniewska and N. Weiss platform by which various signalling pathways modulate channel activity (Leunissen et al. 2013) (Ding et al. 2014) (Laedermann et al. 2013). The network of interactions underlying glycosylation-related regulation of ion channels is grad- ually being discovered. This is of extremely high importance considering that dysregulation of ion channels gives rise to numerous human disorders, either congenital or acquired, the so-called channelopathies (Weiss and Koschak 2014) (Kim 2014), and that the list of inborn defects resulting from defective protein glycosylation (congenital disorders of glycosylation, CDG) is still growing (Scott et al. 2014). The focus of this review is to provide a comprehensive understanding of our current knowledge of the role of glycosylation in ion channel function and physiology. 2 Protein Glycosylation in a Nutshell The biochemical and enzymatic basis of protein glycosylation has recently been extensively reviewed elsewhere (Moremen et al. 2012), and thus we only provide here a succinct overview. Glycans are built from nine monosaccharides – fucose, galactose, N-acetylgalactosamine (GalNAc), glucose, N-acetylglucosamine (GlcNAc), glucuronic acid, mannose, sialic acid and xylose (Fig. 1a). Glycosylation is the enzymatic process mediated by various glycosidases and glycosyl- transferases, as opposed to glycation. Proteins can be O- and N-linked glycosylated. In the case of O-glycosylation, the oligosaccharide is attached to the protein via an oxygen atom on a serine (S) or threonine (T). In contrast, N-glycosylation involves addition of saccharides to an asparagine (N) located within a canonical
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