LRRC55 modulates BK channels to support Purkinje cell plasticity and motor coordination

Large-conductance Ca2+- and voltage-activated K+ (BK) channels are widely expressed, including in the brain where they shape neuronal excitability. Their physiological functions are strongly influenced by cell-type-specific auxiliary subunits. The auxiliary {gamma}3 subunit (LRRC55) enhances BK-channel activation by shifting voltage-dependent gating toward more negative potentials; however, its protein distribution and in vivo function remain unclear. Here, we generated knock-in mice carrying a C-terminal epitope tag on endogenous LRRC55 to map its expression, and Lrrc55 knockout mice to test its function. LRRC55 protein was selectively enriched in cerebellar Purkinje cells. Lrrc55 deletion produced ataxia-like impairments in gait, balance, and coordination. In acute slices, pharmacological BK-channel block with paxilline altered Purkinje cell simple- and complex-spike firing in wild-type mice, whereas these BK-dependent effects were largely absent in Lrrc55 knockouts, indicating that LRRC55 is required for BK channels to shape Purkinje cell firing under these conditions. Moreover, LRRC55 loss disrupted cerebellar synaptic plasticity, abolishing parallel fiber-Purkinje cell long-term potentiation and eliminating climbing fiber-Purkinje cell long-term depression, phenocopying paxilline in wild-type cells. Together, these results identify LRRC55 as a Purkinje-cell-enriched auxiliary subunit that is essential for BK-dependent excitability and plasticity and that supports normal cerebellar motor function. Significance StatementBK channels are important regulators of neuronal firing, but how they are modulated in specific brain regions is poorly understood. We show that the BK {gamma}3 subunit LRRC55 is selectively enriched in cerebellar Purkinje cells and is required for normal motor coordination. Loss of LRRC55 removes BK-dependent modulation of Purkinje cell firing and abolishes two major forms of cerebellar synaptic plasticity, parallel fiber long-term potentiation and climbing fiber long-term depression, while phenocopying pharmacological BK-channel inhibition. These findings reveal an in vivo, cell-type-specific mechanism by which an auxiliary subunit makes BK channels functionally relevant for circuit plasticity and behavior, with implications for understanding cerebellar ataxia.