Figure 11. Neurophysiological implications of Ca_V2.1 CDF.

A, diagram illustrating the role of CDF in homeostatic rate control of Purkinje cells. Increased rate of Purkinje cell spiking elevates global Ca²⁺, facilitating Ca_V2.1 opening via CDF. Increased Ca_V2.1 activity in turn activates colocalized SK channels, resulting in stronger membrane hyperpolarization that then reduces spiking rate. B, similarly, decreased spiking rate leads to lower global Ca²⁺, reduced CDF, and less SK activation, finally resulting in weaker hyperpolarization and restoration of spiking rate. C, Ca²⁺ dose–response curves for CDF (continuous black line) and neurotransmitter secretion (red line). Additionally, Ca²⁺ sensitivity of paired-pulse facilitation due to residual Ca²⁺ (Regehr et al. 1994) (dashed line) shows an additional mechanism specifying the extent of transmitter release. D, generic nerve terminal is modelled as a sphere with Ca_V2.1 channels uniformly expressed on the membrane. A thin shell compartment adjacent to the membrane forms the nanodomain within which the CDF Ca²⁺ sensor CaM, which acts as a channel subunit, actually senses Ca²⁺. Ca²⁺ within the shell compartment can diffuse to and from the much larger cytosolic compartment. The cytosolic compartment is in turn connected to a third and much larger compartment representing the axon branch itself. The Ca²⁺ concentration within this axonal compartment is set at a fixed resting level, and thus serves to returns Ca²⁺ within the terminal back to its resting levels after periods of activity. The parameters for this system are: r_sphere = 8 μm, r_cyto = 7.9 μm, N_chan = 60,000, k_sc = k_cs = 6 × 10⁻¹³ dm³ ms⁻¹, and k_efflux = 6 × 10⁻¹⁴ dm³ ms⁻¹, with the parameters adjusted such that simulations in E match data from Cuttle et al. (1998). Note that the simulated volume is larger than physical terminals because Ca²⁺ buffers are not explicitly modelled here. E, simulations of the system in D in response to 100 Hz step depolarizations to −20 mV. Ca_V2.1 currents are elicited (bottom row) by the voltage stimulation (top row), which results in a build-up of Ca²⁺ in both the shell (second row) and cytosolic (third row) compartments. The increased Ca²⁺ induces CDF of Ca_V2.1 channels, resulting in gradual amplification of I_Ca, Ca_shell and Ca_cyto. F, CDF at steady state is inversely related to stimulation frequency (blue circles and continuous line), largely due to frequency-dependent accumulation of residual Ca²⁺ (100 Hz example in red).