The L-type calcium channel current modulation mechanism: the plot thickens and fogs

Abstract

Stressful situations provoke the fight-or-flight response, incurring rapid elevation of cardiac output via activation of protein kinase A (PKA). In this issue of the JCI, Yang et al. focus on the L-type calcium channel complex (LTCC), and their findings require reexamination of dogmatic principles. LTCC phosphorylation sites identified and studied to date are dispensable for PKA modulation of LTCC; however, a CaVβ2-CaV1.2 calcium channel interaction is now shown to be required. Yang et al. suggest a new hypothesis that LTCC modulation involves rearrangement of auxiliary proteins within the LTCC. However, we still do not know the targets of PKA that mediate LTCC modulation.

Figure 1. Ca_Vβ₂-Ca_V1.2 interaction is not required for forward trafficking, but is required for Ca_V1.2 modulation by PKA.

(A) Old dogma: Ca_Vβ-Ca_Vα interaction on the Golgi apparatus promotes forward trafficking. Ca_V1.2 in the transverse tubules is modulated by one or more phosphoregulatory sites on Ca_V1.2 and/or Ca_Vβ₂. (B) New paradigm: Ca_Vβ-Ca_Vα interaction is not required for forward trafficking, and in the transverse tubules Ca_V1.2 modulation requires Ca_Vβ, and perhaps additional accessory subunits.