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The intracellular loops that interlink the four transmembrane domains of Ca 2+ - and Na + -channels (Ca v , Na v ) have critical roles in numerous forms of channel regulation. In particular, the intracellular loop that joins repeats I and II (I–II loop) in high voltage-activated (HVA) Ca 2+  channels possesses the binding site for Ca v β subunits and plays significant roles in channel function, including trafficking the α 1  subunits of HVA channels to the plasma membrane and channel gating. Although there is considerable divergence in the primary sequence of the I–II loop of Ca v 1/Ca v 2 HVA channels and Ca v 3 LVA/T-type channels, evidence for a regulatory role of the I–II loop in T-channel function has recently emerged for Ca v 3.2 channels. In order to provide a comprehensive view of the role this intracellular region may play in the gating and surface expression in Ca v 3 channels, we have performed a structure-function analysis of the I–II loop in Ca v 3.1 and Ca v 3.3 channels using selective deletion mutants. Here we show the first 60 amino acids of the loop (post IS6) are involved in Ca v 3.1 and Ca v 3.3 channel gating and kinetics, which establishes a conserved property of this locus for all Ca v 3 channels. In contrast to findings in Ca v 3.2, deletion of the central region of the I–II loop in Ca v 3.1 and Ca v 3.3 yielded a modest increase (+30%) and a reduction (−30%) in current density and surface expression, respectively. These experiments enrich our understanding of the structural determinants involved in Ca v 3 function by highlighting the unique role played by the intracellular I–II loop in Ca v 3.2 channel trafficking, and illustrating the prominent role of the gating brake in setting the slow and distinctive slow activation kinetics of Ca v 3.3.

I–II Loop Structural Determinants in the Gating and Surface Expression of Low Voltage-Activated Calcium Channels