Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels

Abstract

Large conductance, calcium-and voltage-activated potassium (BK) channels control excitability in many tissues and are regulated by several protein kinases and phosphatases that remain associated with the channels in cell-free patches of membrane. Here, we report the identification of a highly conserved, non-canonical, leucine zipper (LZ1) in the C terminus of mammalian BK channels that is required for cAMP-dependent protein kinase ( Reversible protein phosphorylation represents a fundamental cellular regulatory mechanism to control the activity and function of plasma membrane ion channels (1). The co-ordination, specificity, and compartmentalization of ion channel regulation by reversible protein phosphorylation is facilitated by assembly with signaling complexes comprising cognate protein kinases and protein phosphatases. Assembly of ion channels with signaling complexes typically results from multiple protein-protein interactions mediated by distinct interaction domains (2) allowing signaling molecules to interact directly with an ion channel or indirectly as part of a higher order complex.Large conductance calcium-and voltage-activated potassium (BK) channels have been widely exploited as models of ion channel regulation by reversible protein phosphorylation; however, the molecular basis for kinase and phosphatase assembly with the BK channel is largely unknown

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…More recent experiments have identified a multi-protein signalling complex that is formed from a direct association of the BK Ca a subunit, b 2 -adrenoceptor and AKAP79/150 (now classified as AKAP5) through a mechanism that may involve leucine-zipper protein-protein interactions [101,102]. This unique signalling complex may also include an L-type voltagegated Ca 2+ channel (Ca v 1.2), resulting in a highly localised signalosome that mediates Ca 2+ -and phosphorylation-dependent modulation of BK Ca currents [101].…”

Regulation of STREX exon large conductance, calcium-activated potassium channels by the β4 accessory subunit

“…Here we measured the combined effect of both STREX and the β4 subunit. The experimental approach was to measure responses to dephosphorylation by alkaline phosphatase followed by cAMP + ATP application to measure effects of pKAdependent phosphorylation (BK channels in HEK cells have pKA pre-tethered to the channel and therefore do not require application of the catalytic enzyme (Tian et al, 2001, Tian et al, 2003). Because all data was paired, we could measure both effects on steady-state values (Fig.…”

Identification and Functional Characterization of Ankyrin-Repeat Family Protein ANKRA as a Protein Interacting with BKCaChannel

“…Recently, it was reported that ␤2 adrenergic receptor could simultaneously interact with both BK Ca and L-type Ca 2ϩ channels in vivo (Liu et al, 2004). Among intracellular signaling molecules in vertebrate, protein kinases and phosphatases, including PKA, protein kinase G, Src tyrosine kinase, Syk tyrosine kinase, focal adhesion kinase, and protein phosphatase 2A are most intensively studied as modulators of BK Ca channels functions (Dworetzky et al, 1996;Sansom et al, 1997;Alioua et al, 1998;Ling et al, 2000;Alioua et al, 2002;Rezzonico et al, 2002Rezzonico et al, , 2003Tian et al, 2003). Recently, Syntaxin1A and ␤-catenine also have been reported as direct binding partners of BK Ca channels.…”