A molecular model of low-voltage-activated calcium conductance

1. T-type or low-voltage-activated Ca2+ channels (IT) expressed in the mammalian thalamus play an important physiological role in the induction of membrane potential oscillations and in the regulation of the timing of synaptic signaling. On the basis of recent molecular studies on Ca2+, Na+, and K+ channels, a structure-kinetic model has been proposed for IT. 2. The model considers that the pore-opening process of IT is governed by three of the four protein domains that are arranged asymmetrically across the membrane plane. The three cytoplasmic linkers connecting individual channel domains serve as inactivation gates. On a membrane voltage change, each domain may engage independently into a sequential, thermodynamically coupled conformational change, thereby causing channel activation and inactivation. 3. A linear Marcov chain reaction with coupled channel activation and inactivation was adopted to test the kinetic feasibility of this trimeric model in a single-compartmental thalamic cell. The differential equations for voltage-dependent rate constants and transitional rates were solved to produce macroscopic T-type Ca2+ current. 4. Our simulation results indicate that this novel structure-kinetic model produces excellent predictions of the macroscopic behaviors of IT, and, more importantly, it provides some new insights into the microscopic mechanism underlying channel recovery.