MaxiK channel partners: physiological impact

Abstract

The basic functional unit of the large-conductance, voltage- and Ca2+-activated K+ (MaxiK, BK, BKCa) channel is a tetramer of the pore-forming alpha-subunit (MaxiKalpha) encoded by a single gene, Slo, holding multiple alternative exons. Depending on the tissue, MaxiKalpha can associate with modulatory beta-subunits (beta1-beta4) increasing its functional diversity. As MaxiK senses and regulates membrane voltage and intracellular Ca2+, it links cell excitability with cell signalling and metabolism. Thus, MaxiK is a key regulator of vital body functions, like blood flow, uresis, immunity and neurotransmission. Epilepsy with paroxysmal dyskinesia syndrome has been recognized as a MaxiKalpha-related disorder caused by a gain-of-function C-terminus mutation. This channel region is also emerging as a key recognition module containing sequences for MaxiKalpha interaction with its surrounding signalling partners, and its targeting to cell-specific microdomains. The growing list of interacting proteins highlights the possibility that associations with the C-terminus of MaxiKalpha are dynamic and depending on each cellular environment. We speculate that the molecular multiplicity of the C-terminus (and intracellular loops) dictated by alternative exons may modulate or create additional interacting sites in a tissue-specific manner. A challenge is the dissection of MaxiK macromolecular signalling complexes in different tissues and their temporal association/dissociation according to the stimulus.

Figure 1. MaxiK channel topological characteristics

A, protein topology of MaxiKα subunit. Arrows mark boundaries of translated constitutive exons (1–27). Asterisks, sites of splice variation. Green asterisk, site of STREX splicing. Dashed blue line, string of asparate residues forming the ‘Ca²⁺ bowl’. Dashed square, RCK domain. B and C, model (top view) of tetrameric assembly showing K⁺ in the pore with and without β-subunits and proteins interacting at the C-terminus.

Figure 2. MaxiK–GPCR functional coupling via Src tyrosine kinase and possible partners in smooth muscle microdomains

A, aortic contraction by 5-hydroxytryptamine (5-HT) is reversed by an inhibitor of Src tyrosine kinase (PP2) in a dose-dependent manner demonstrating Src role in 5-HT-induced contraction. Bar, 10 milli Newtons (mNt). B, MaxiK blockade with Iberiotoxin (IbTx) hampers PP2-induced relaxation highlighting MaxiK–GPCR coupling via Src. C, hypothetical diagram of possible MaxiK interactions with partner proteins in caveolae domains where signals are integrated and transduced for a contractile response. GPCR, G-protein coupled receptor; Cav-1, caveolin-1; Gα,β,γ, G-protein α-, β- and γ-subunits. Panels A and B reproduced with permission from Alioua et al. PNAS 99, 14560–14565, Copyright 2002 National Academy of Sciences, USA (Alioua et al. 2002).