Proteomics of Ca2+-mediated signaling - PNAS Cover Feature

Müller CS, Haupt A, Bildl W, Schindler J, Knaus HG, Meissner M, Rammner B, Striessnig J, Flockerzi V, Fakler B, Schulte U

Local Ca²⁺ signaling occurring within nanometers of voltage-gated Ca²⁺ (Cav) channels is crucial for CNS function, yet the molecular composition of Cav channel nano-environments is largely unresolved. Here, we used a proteomic strategy combining knockout-controlled multiepitope affinity purifications with high-resolution quantitative MS for comprehensive analysis of the molecular nano-environments of the Ca_v2 channel family in the whole rodent brain.

The analysis shows that C_av2 channels, composed of pore-forming α₁ and auxiliary β subunits, are embedded into protein networks that may be assembled from a pool of ∼200 proteins with distinct abundance, stability of assembly, and preference for the three C_av2 subtypes.

The majority of these proteins have not previously been linked to C_av channels; about two-thirds are dedicated to the control of intracellular Ca²⁺ concentration, including G protein-coupled receptor-mediated signaling, to activity-dependent cytoskeleton remodeling or Ca²⁺-dependent effector systems that comprise a high portion of the priming and release machinery of synaptic vesicles.

The identified protein networks reflect the cellular processes that can be initiated by C_av2 channel activity and define the molecular framework for organization and operation of local Ca²⁺ signaling by C_av2 channels in the brain.

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