Large-conductance calcium-activated potassium (BK) channels regulate respiratory, metabolic and behavioural responses...

Large-conductance Ca²⁺-activated K⁺ (BK) channels regulate excitability across physiological systems, and BK channelopathies cause neurodevelopmental delay, cognitive disability and structural brain malformations. The firing rate response of CO₂/pH chemosensitive neurones has been suggested to be modulated by the BK channels' activity, which would function as a 'brake' on the chemosensitive response. Thus, our study examined the role of BK channels in ventilatory, metabolic and behavioural responses under normocapnic and hypercapnic conditions in wild-type (Slo1^+/+) and BK channel knockout (Slo1^-/-) mice of both sexes during postnatal development. Additionally, the electrophysiological properties and chemosensitivity of locus coeruleus (LC) neurones in Slo1^+/+ and Slo1^-/- mice of both sexes were studied. Our data show that Slo1^-/- mice displayed multiple changes in respiratory and behavioural phenotypes. Across sexes, Slo1^-/- animals experienced a higher rate of apnoeic events: females exhibited more spontaneous apnoeas, whereas males showed more post-sigh apnoeas and sighs. Slo1^-/- males also demonstrated an exaggerated chewing reflex. Behaviourally, Slo1^-/- females spent less time in the periphery and more time in the centre of the open-field arena compared with wild-type females. During the panic-inducing 20% CO₂ challenge, both sexes showed reduced defensive responses, including fewer escape jumps. Lastly, LC neurones from Slo1^-/- males exhibited an enhanced chemosensitive response to CO₂ compared with controls. These findings demonstrate that loss of BK channels disrupts respiratory stability, alters behavioural responses and enhances central CO₂ chemosensitivity in an age- and sex-dependent manner. KEY POINTS: Absence of BK channels increases breathing variability and apnoea events during postnatal development. BK channel deletion leads to an augmented hypercapnic ventilatory response during postnatal development in a sex-dependent manner. Loss of BK channels reduces panic-like behavioural responses during panic attack induction. LC neurones lacking BK channels exhibit increased CO₂ chemosensitivity in male mice.