Competitive Calcium Binding: Implications for Dendritic Calcium Signaling

Action potentials evoke calcium transients in dendrites of neocortical pyramidal neurons with time constants of <100 ms at physiological temperature. This time period may not be sufficient for inflowing calcium ions to equilibrate with all present Ca²⁺-binding molecules. We therefore explored nonequilibrium dynamics of Ca²⁺ binding to numerous Ca²⁺ reaction partners within a dendritelike compartment using numerical simulations. After a brief Ca²⁺ influx, the reaction partner with the fastest Ca²⁺ binding kinetics initially binds more Ca²⁺ than predicted from chemical equilibrium, while companion reaction partners bind less. This difference is consolidated and may result in bypassing of slow reaction partners if a Ca²⁺ clearance mechanism is active. On the other hand, slower reaction partners effectively bind Ca²⁺ during repetitive calcium current pulses or during slower Ca²⁺ influx. Nonequilibrium Ca²⁺ distribution can further be enhanced through strategic placement of the reaction partners within the compartment. Using the Ca²⁺ buffer EGTA as a competitor of fluo-3, we demonstrate competitive Ca²⁺ binding within dendrites experimentally. Nonequilibrium calcium dynamics is proposed as a potential mechanism for differential and conditional activation of intradendritic targets.