Trafficking of potassium channels
Introduction
We are currently witnessing a synthesis between traditionally separate areas of research, that is, physiology and cell biology. The challenge is to understand how basic cellular machinery (often conserved from yeast to man) functions in the context of highly specialized tissues or organs (such as the brain) or in response to changing conditions (such as neuronal activity or ischemia). Potassium channels are multimeric, polytopic membrane proteins with crucial functions in cellular ion homeostasis and excitability. Their correct functioning depends not only on the regulation of their biophysical properties but also on the fine-tuning of their subcellular localization and number of cell surface copies. Several recent reviews cover biogenesis, specific trafficking signals or mechanisms, in addition to the trafficking of particular subclasses of potassium channels [1, 2, 3, 4, 5]. Here, we highlight new information on trafficking from all families of potassium channels with a particular focus on new technical approaches and trafficking in specialized cell types.
Section snippets
Biogenesis
In a similar way to most polytopic membrane proteins traveling the secretory pathway, ion channels start their life at the endoplasmic reticulum (ER) using the translocon for translocation and integration into the lipid bilayer [6]. However, for many channels their oligomerization state and the binding of auxiliary subunits crucially affect the first trafficking steps, for example, sorting from the ER to the Golgi apparatus [3]. This can be viewed as part of cellular quality control [7], but
Trafficking determinants
The dissection of trafficking determinants in a polytopic membrane protein can reveal peptide trafficking motifs (often recognized by vesicle coat proteins) or larger domains that influence or govern the movement of the cargo protein along the secretory or endocytic pathway. Arginine-based ER localization signals are peptide trafficking signals involved in the heteromultimeric assembly of KATP channels and other ion channels and receptors [3]. Employing a series of carefully designed reporter
Accessory proteins and multiprotein complexes
Exciting progress has recently been made in elucidating the supermolecular complex that underlies rapidly inactivating potassium channels in the heart (ITO) and in neurons (ISA). The search for accessory subunits modulating the biophysical properties of Kv4 potassium channels to match native currents has previously identified cytosolic accessory subunits of the neuronal calcium sensor family, KChIPs [26]. Nadal et al. [27••] now present the co-immunopurification of an additional
Neuronal trafficking
How is the cellular trafficking machinery adopted to the needs of highly specialized cell types such as neurons? This fascinating problem is the subject of recent reviews [45, 46]. Complementary studies have investigated the dendritic targeting of Kv4.2 [47•] and the axonal targeting of Kv1.2 [48••]. Rivera et al. [47•] identify a C-terminal 16 amino acid trafficking determinant containing a di-leucine motif necessary and sufficient for dendritic targeting of the channel protein. Interestingly,
Regulation
As pointed out by Horton and Ehlers [45], sorting into membrane microdomains along axonal and dendritic segments represents an additional mechanism by which neuronal compartments are endowed with specific functional properties. Interestingly, Misonou et al. [49••] find the occurrence of Kv2.1 in microdomains on the somata and dendrites of pyramidal neurons to be altered by excitatory neurotransmission. The study beautifully moves from brain sections of rats subjected to experimentally induced
Conclusions
The oligomeric composition of potassium channels, their recruitment into multiprotein complexes, and the number of copies at the plasma membrane crucially affect cellular excitability and contribute to the rich physiology of this large class of channel proteins. For Kv channels, insight into these parameters ranges from a structural understanding of supermolecular complexes through detailed information on protein folding to sophisticated sorting and regulatory mechanisms in the brain. Solid
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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Cited by (42)
Distinctive role of K<inf>V</inf>1.1 subunit in the biology and functions of low threshold K<sup>+</sup> channels with implications for neurological disease
2016, Pharmacology and TherapeuticsCitation Excerpt :Studies of KV1 homo-tetramers in expression systems, in addition to commonalities have revealed differences in the biophysical and pharmacological properties, which in hetero-tetramers equilibrate between contributing subunits (Akhtar et al., 2002; Sokolov et al., 2007; Bagchi et al., 2014). In addition to electrophysiological properties, the molecular composition of KV1 channels is known to control their mobility and targeting to specific neuronal compartments with surface expression (Manganas & Trimmer, 2000; Manganas et al., 2001b; Heusser & Schwappach, 2005; Vacher et al., 2007b; Vacher et al., 2008). Although in heterologous systems all combinations of KV1 subunits yield K+ currents, native channels from crude forebrain extracts and synaptosomes have revealed a predominance of certain subunits and their combinations over others (Koch et al., 1997; Shamotienko et al., 1997; Coleman et al., 1999; Wang et al., 1999).
Identification of Ppk26, a DEG/ENaC Channel Functioning with Ppk1 in a Mutually Dependent Manner to Guide Locomotion Behavior in Drosophila
2014, Cell ReportsCitation Excerpt :These specific null alleles of ppk26 and ppk1 will be useful for future functional studies of these two coexpressed DEG/ENaC channel subunits, as well as analysis of genetic interactions. Ion channels and receptors composed of multiple subunits are often assembled in the endoplasmic reticulum (ER), and traffic as multimers to their site of function (Heusser and Schwappach, 2005; Muth and Caplan, 2003). Thus, lack of one of the subunits may prevent the others from reaching their destination.
Self-directed assembly and clustering of the cytoplasmic domains of inwardly rectifying Kir2.1 potassium channels on association with PSD-95
2011, Biochimica et Biophysica Acta - BiomembranesN-linked glycosylation determines cell surface expression of two-pore-domain K<sup>+</sup> channel TRESK
2010, Biochemical and Biophysical Research CommunicationsCitation Excerpt :A significant decrease in fluorescence signal was also detected for the N96Q mutant of hTRESK although the asparagine at this position did not show N-glycan modification in the biochemical assay. However, efficient membrane transport of proteins does not only depend on N-glycosylation but was also found to be regulated by other motifs that are located in different domains of ion channels and receptors [18,19]. In K2P channels the extracellular M1P1 linker loop is involved in the assembly of functional dimeric channels [20] that are formed during maturation in the Golgi and the trans-Golgi network.
How do ER export motifs work on ion channel trafficking?
2009, Current Opinion in Plant BiologyPotassium Channel Regulation
2009, Encyclopedia of Neuroscience