Paul J. Adams

Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies.

Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit distinct spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming α1-subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in two predominant splice variants of the neuronal CaV2.1 P/Q-type channel. All three FHM-1 mutations cause a greater hyperpolarizing shift in voltage-dependent properties when expressed in the short carboxyl terminus variant (CaV2.1 Δ47) compared to the long variant (CaV2.1 +47). Furthermore, the FHM-1 mutations also exhibit differential splice variant-specific effects on recovery from inactivation and accumulation of inactivation during tonic and burst firing. Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies.

Towards a Unified Theory of Calmodulin Regulation (Calmodulation) of Voltage-Gated Calcium and Sodium Channels

Voltage-gated Na and Ca(2+) channels represent two major ion channel families that enable myriad biological functions including the generation of action potentials and the coupling of electrical and chemical signaling in cells. Calmodulin regulation (calmodulation) of these ion channels comprises a vital feedback mechanism with distinct physiological implications. Though long-sought, a shared understanding of the channel families remained elusive for two decades as the functional manifestations and the structural underpinnings of this modulation often appeared to diverge. Here, we review recent advancements in the understanding of calmodulation of Ca(2+) and Na channels that suggest a remarkable similarity in their regulatory scheme. This interrelation between the two channel families now paves the way towards a unified mechanistic framework to understand vital calmodulin-dependent feedback and offers shared principles to approach related channelopathic diseases. An exciting era of synergistic study now looms.

A rendezvous with the queen of ion channels: Three decades of ion channel research by David T Yue and his Calcium Signals Laboratory

David T. Yue was a renowned biophysicist who dedicated his life to the study of Ca2+ signaling in cells. In the wake of his passing, we are left not only with a feeling of great loss, but with a tremendous and impactful body of work contributed by a remarkable man. Davids research spanned the spectrum from atomic structure to organ systems, with a quantitative rigor aimed at understanding the fundamental mechanisms underlying biological function. Along the way he developed new tools and approaches, enabling not only his own research but that of his contemporaries and those who will come after him. While we cannot hope to replicate the eloquence and style we are accustomed to in Davids writing, we nonetheless undertake a review of Davids chosen field of study with a focus on many of his contributions to the calcium channel field.

Large Ca2+-dependent facilitation of CaV2.1 channels revealed by Ca2+photo-uncaging: Large CDF of CaV2.1 channels revealed by Ca2+photo-uncaging

CaV2.1 channels constitute a dominant Ca2+ entry pathway into brain neurons, triggering downstream Ca2+‐dependent processes such as neurotransmitter release. CaV2.1 is itself modulated by Ca2+, resulting in activity‐dependent enhancement of channel opening termed Ca2+‐dependent facilitation (CDF). Real‐time Ca2+ imaging and Ca2+ uncaging here reveal that CDF turns out to be strikingly faster, more Ca2+ sensitive, and larger than anticipated on previous grounds. Robust resolution of the quantitative profile of CDF enables deduction of a realistic biophysical model for this process. These results suggest that CaV2.1 CDF would figure most prominently in short‐term synaptic plasticity and cerebellar Purkinje cell rhythmicity.