Abstract
Auxiliary subunits are non-conducting, modulatory components of the multi-protein ion channel complexes that underlie normal neuronal signaling. They interact with the pore-forming α-subunits to modulate surface distribution, ion conductance, and channel gating properties. For the somatodendritic subthreshold A-type potassium (ISA) channel based on Kv4 α-subunits, two types of auxiliary subunits have been extensively studied: Kv channel-interacting proteins (KChIPs) and dipeptidyl peptidase-like proteins (DPLPs). KChIPs are cytoplasmic calcium-binding proteins that interact with intracellular portions of the Kv4 subunits, whereas DPLPs are type II transmembrane proteins that associate with the Kv4 channel core. Both KChIPs and DPLPs genes contain multiple start sites that are used by various neuronal populations to drive the differential expression of functionally distinct N-terminal variants. In turn, these N-terminal variants generate tremendous functional diversity across the nervous system. Here, we focus our review on (1) the molecular mechanism underlying the unique properties of different N-terminal variants, (2) the shaping of native ISA properties by the concerted actions of KChIPs and DPLP variants, and (3) the surprising ways that KChIPs and DPLPs coordinate the activity of multiple channels to fine-tune neuronal excitability. Unlocking the unique contributions of different auxiliary subunit N-terminal variants may provide an important opportunity to develop novel targeted therapeutics to treat numerous neurological disorders.
Highlights
TO ISA The membranes of neurons contain multiple sets of voltagesensitive K+ (Kv) channels that open and close in response to changes in membrane potential, giving rise to outward K+ currents with differing voltage dependence, kinetic properties, and pharmacological sensitivities
We focus our review on (1) the molecular mechanism underlying the unique properties of different N-terminal variants, (2) the shaping of native ISA properties by the concerted actions of Kv channelinteracting proteins (KChIPs) and dipeptidyl peptidase-like proteins (DPLPs) variants, and (3) the surprising ways that KChIPs and DPLPs coordinate the activity of multiple channels to fine-tune neuronal excitability
In addition to KChIP and DPLP proteins, various published reports suggest that additional ancillary, cytoskeletal, and molecular chaperone proteins may interact with the ISA channel complex, including Kvβ subunit, Navβ1 subunit, MinK-related protein 1 (MiRP1), kinesin isoform Kif17, Kv channel-associated protein (KChAP), post-synaptic density protein 95 (PSD-95), and filamin (Petrecca et al, 2000; Yang et al, 2001; Zhang et al, 2001; Deschenes and Tomaselli, 2002; Wong et al, 2002; Marionneau et al, 2012a; Table 1)
Summary
TO ISA The membranes of neurons contain multiple sets of voltagesensitive K+ (Kv) channels that open and close in response to changes in membrane potential, giving rise to outward K+ currents with differing voltage dependence, kinetic properties, and pharmacological sensitivities. Later characterized in detail by Connor and Stevens (1971b) and Neher (1971), ISA activates rapidly in the subthreshold range of membrane potentials but rapidly inactivates. Due to its high density in the dendrites and its rapid activation, ISA suppresses action potential backpropagation (Hoffman et al, 1997). In regions of the dendritic tree that experienced recent depolarizing synaptic activity sufficient to inactivate ISA, the backpropagating action potential remains large and induces a large influx of Ca2+ that is critical for longterm potentiation (LTP; Johnston et al, 2003). The identification of the Shaker gene mutants led to the discovery of the first voltage-gated K+ channel, Shaker, and the identification of other subfamilies of Kv channels in the fly Frontiers in Cellular Neuroscience www.frontiersin.org
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