Neurological consequences of human calmodulin mutations

Neurological consequences of human calmodulin mutationsWhen calcium ions enter the cytosol, it is a stimulatory signal for cellular events.The calcium sensor calmodulin picks up the change in calcium concentration and relays this information to its more than 300 downstream interaction partners.In this way, calmodulin affects cellular processes such as fertilization, muscle contraction, neuronal firing, and apoptosis.That is, calmodulin is involved in (nearly) everything!The significance of calmodulin is emphasized by the fact that we all carry three different genes (CALM1,2,3) on different chromosomes that encode the exact same calmodulin protein, and these are all expressed in all cell types.Moreover, throughout vertebrate evolution, the protein sequence has remained completely unchanged.Although calmodulin has been a topic of research since the early 1970s, the first human mutations were not discovered until 2012 (Nyegaard et al., 2012).Here, the link between human calmodulin mutations and cardiac arrhythmia was established.Cardiologists around the world have since then identified calmodulin mutations in arrhythmia patients, and in vitro studies have established the main molecular mechanism.Briefly, calmodulin mutations affect the calcium-binding affinity of calmodulin and/or the ability of calmodulin to bind and regulate key cardiac ion channels.Calmodulin mutations thus primarily impair calcium signals and the cardiac action potential and not the actomyosin contractility in itself.The molecular details of these disruptions have been reviewed elsewhere (Jensen et al., 2018;Nyegaard and Overgaard, 2019).However, the link between calmodulin mutations and cardiac arrhythmia remains puzzling.Calmodulin is expressed in all cells of the body, at very high levels in the brain, and it is involved in numerous signaling pathways.Nonetheless, mutations in patients seem to only affect specific interaction partners in cardiomyocytes, a highly specialized cell type.