Figure 6. STREX is required for glucocorticoid regulation of BK channels.

A, schematic illustrating that BK channels containing the STREX insert are targets for both protein kinase A (PKA) and glucocorticoid signalling pathways. PKA closely associated with membrane patches is activated by cyclic 3′,5′-adenosine monophosphate (cAMP). Steroids, such as the synthetic glucocorticoid dexamethasone, activate intracellular glucocorticoid receptors (GR) to regulate gene transcription. GR induced de novo synthesis of unidentified (X) proteins that block PKA-dependent regulation of STREX-containing channels through modification of protein phosphatase 2A-like (PPase) activity closely associated with the membrane patch in dexamethasone-treated cells. B, schematic summarising the effect of PKA and glucocorticoids on the different BK channel splice variant constructs used in this study. The effect of PKA is indicated by activation (up arrow) or inhibition (down arrow) of channel activity. The ability of dexamethasone to block the PKA-induced regulation of BK channel activity is indicated. The STREX insert is essential for glucocorticoid-mediated regulation of BK channel activity irrespective of the functional effect of PKA on channel activity (activation or inhibition) for the different constructs. Serine residues essential for PKA-mediated activation of channel activity (conserved S₈₆₉ in C-terminal tail of channel) and PKA-mediated inhibition (S₄ in the STREX insert) are indicated.