We are interested in how specific ion channels influence information coding at the membrane, cellular, circuit/organ, and whole animal levels. We study a unique ion channel, the large conductance, Ca2+-activated K+ channel (BK). BK channels are allosterically regulated by voltage and Ca2+ and play prominent roles in neuronal and muscle physiology, modulating action potential repolarization, afterhyperpolarizations, and repetitive firing. Although BK channels have been extensively studied at the biophysical level, less is known about their roles in non-excitable cell types or intact physiological systems. In my lab, we combine the genetic manipulation of ion channels with electrophysiology and behavior. I made a deletion of the BK channel alpha subunit in mouse (Slo-/- or Kcnma1-/-).

Identifying novel roles for BK channels

BK channels are highly expressed in subsets of central neurons and smooth muscle, and are also present in skeletal muscle, neuroendocrine tissues, peripheral neurons, and kidney. Unlike the voltage-gated K+ channel family, there is only one gene that encodes the BK channel, and Kcnma1-/- mice display a surprising number of phenotypes at the cellular and behavioral levels. This lack of compensation or redundancy has enabled us to use the BK channel deletion mouse as a general mechanism for perturbing signaling in a variety of pathways. To identify new systems in which BK channels play dominant roles, we are conducting phenotypic screens in Kcnma1-/- mice with global and tissue-specific conditional deletions of the BK channel.

BK channels regulate excitability in the brain’s intrinsic clock

Circadian physiology is an ideal model system for studying information coding. Daily behavioral and physiological rhythms (~ 24 hrs) are a universal trait of animals, vital for adaptation to their environment and overall fitness. In mammals, lesion and transplantation studies have localized the principal circadian pacemaker to the suprachiasmatic nucleus (SCN) of the hypothalamus, identifying a discrete neural substrate for a complex behavior. Individual SCN neurons exhibit daily oscillations in spontaneous action potential firing. My lab studies how the daily variation in spontaneous firing rate is generated and how patterns of SCN activity confer circadian timing to behaviors. We recently identified a role for Kcnma1, the gene that encodes the BK Ca2+-activated K+ channel, in pacemaker function. Kcnma1-/- mice have degraded circadian behavioral and physiological rhythms, and their SCN neurons exhibit aberrant daily action potential rhythms.