The leucine-rich repeat domains of BK channel auxiliary γ subunits regulate their expression, trafficking, and channel-modulation functions

Abstract

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High-resolution structures illuminate key principles underlying voltage and LRRC26 regulation of Slo1 channels

“…This suggests that, if the structural interaction between the LRRDs is disrupted, it impedes the ability of γ1 to associate with Slo1. Consistent with this, deletion of the LRRD segments or replacing it with unrelated globular domains in the context of γ1 alters the functional effects of mutant subunits 67 probably due to aberrant assembly. Designer constructs, in which the γ1-TM replaces the second transmembrane helix of β subunits, are however able to efficiently assemble with and modulate Slo1, even without the LRRD 67,75 .…”

“…Consistent with this, deletion of the LRRD segments or replacing it with unrelated globular domains in the context of γ1 alters the functional effects of mutant subunits 67 probably due to aberrant assembly. Designer constructs, in which the γ1-TM replaces the second transmembrane helix of β subunits, are however able to efficiently assemble with and modulate Slo1, even without the LRRD 67,75 . Thus, while the LRRDs are important for the association of native γ subunits with Slo1, they are likely vestigial for their modulatory functions.…”

“…N147 is on the external surface of LRRD, directed away from the channel and the membrane. In the absence of glycosylation of γ1, gating shifts are not observed 67 , but it is not known whether this is a lack of function or assembly.…”

“…While the LRRD of γ1 plays a distinct and important role in the Slo1: γ1 complex assembly, the γ1-TM is critical for assembly as well as Slo1 functional regulation 14,67,72,75 . The γ1-TM kink in particular might be a critical structural element necessary for its modulatory effects.…”

BK channels in microglia

“…Large-conductance calcium-and voltage-dependent potassium (BK) channels are composed of pore-forming α subunits (Slo1, KCNMA1) and auxiliary subunits, including β1 through β4 (KCNMB1 through KCNMB4), γ1 through γ4 (LRRC26, LRRC52, LRRC55, LRRC38), and LINGO1 through LINGO4 [1][2][3][4][5][6][7]. BK channels are ubiquitously distributed in the body and play vital roles in various physiological and pathological processes [8,9].…”