Abstract
Voltage-gated K+ (Kv) channels play important roles in regulating neuronal excitability. Kv channels comprise four principal α subunits, and transmembrane and/or cytoplasmic auxiliary subunits that modify diverse aspects of channel function. AMIGO-1, which mediates homophilic cell adhesion underlying neurite outgrowth and fasciculation during development, has recently been shown to be an auxiliary subunit of adult brain Kv2.1-containing Kv channels. We show that AMIGO-1 is extensively colocalized with both Kv2.1 and its paralog Kv2.2 in brain neurons across diverse mammals, and that in adult brain, there is no apparent population of AMIGO-1 outside of that colocalized with these Kv2 α subunits. AMIGO-1 is coclustered with Kv2 α subunits at specific plasma membrane (PM) sites associated with hypolemmal subsurface cisternae at neuronal ER:PM junctions. This distinct PM clustering of AMIGO-1 is not observed in brain neurons of mice lacking Kv2 α subunit expression. Moreover, in heterologous cells, coexpression of either Kv2.1 or Kv2.2 is sufficient to drive clustering of the otherwise uniformly expressed AMIGO-1. Kv2 α subunit coexpression also increases biosynthetic intracellular trafficking and PM expression of AMIGO-1 in heterologous cells, and analyses of Kv2.1 and Kv2.2 knockout mice show selective loss of AMIGO-1 expression and localization in neurons lacking the respective Kv2 α subunit. Together, these data suggest that in mammalian brain neurons, AMIGO-1 is exclusively associated with Kv2 α subunits, and that Kv2 α subunits are obligatory in determining the correct pattern of AMIGO-1 expression, PM trafficking and clustering.
Highlights
Mammalian voltage-gated potassium (Kv) channels function as macromolecular assemblies of four voltage-sensing and pore-forming principal or α subunits (Trimmer, 2015)
These results suggest that the immunolabeling with these newly generated AMIGO-1 antibodies in immunohistochemistry analyses on mouse brain sections is specific for AMIGO-1, and that AMIGO-1 is primarily present on the cell bodies and proximal dendrites of neurons
There is no apparent AMIGO-1 population outside of that colocalized with Kv2 α subunits that would suggest a role for AMIGO-1 in adult brain outside of being an auxiliary subunit of Kv2 channels
Summary
Mammalian voltage-gated potassium (Kv) channels function as macromolecular assemblies of four voltage-sensing and pore-forming principal or α subunits (Trimmer, 2015). Kv channel auxiliary subunits impact Kv channel activity indirectly through effects on protein assembly and folding, regulation of biosynthetic intracellular trafficking, clustering at specific plasma membrane (PM) sites, and by influencing rates of endocytic recycling and degradation (Li et al, 2006; Pongs and Schwarz, 2010; Vacher and Trimmer, 2011) They can exert profound effects on the function of Kv channels by impacting diverse aspects of channel gating (Li et al, 2006; Pongs and Schwarz, 2010; Vacher and Trimmer, 2011). Certain ion channel auxiliary subunits have been shown to exhibit functions independent of their role as auxiliary subunits, most notably the β subunits of voltage-gated sodium channels that function as cell adhesion molecules (Kruger and Isom, 2016)
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