Cardiac Gα_i2 Protein Function and Regulation of High-Voltage-Gated L-type Calcium Channels

Abstract

It has been proposed that the highly homologous and pertussis toxin (PTX)-sensitive cardiac Gα_i isoforms, Gα_i2 and Gα_i3, are functionally distinct. Moreover, they are upregulated in heart failure. However, their stimulation by the parasympathic and sympathic nervous system and their effects on cardiac L-type calcium channel regulation remain unclear. In this study, the Gα_i isoform-specific modulation of L- type calcium channels at the whole-cell level is investigated, using cardiomyocytes from mice lacking either Gα_i2 (Gα_i2-/-) or Gα_i3 (Gα_i3-/-) protein. In these cardiomyocytes, the other Gα_i isoform is enhanced on mRNA and protein levels, whereas channel expression levels of Ca_vα and Ca_vβ subunits are nearly unchanged. Furthermore, subtype-specific signalling effects are detected. In particular, calcium current density in Gα_i2-/- cardiomyocytes is significantly decreased, whereas it is significantly increased in Gα_i3-/- cells as compared to control animals. Interestingly, only genetic or PTX-mediated abolition of Gα_i2 function causes a steady-state inactivation shift towards hyperpolarized potentials and a delayed calcium current recovery. This novel Gα_i2-associated effect is reflected by alterations in calcium channel kinetics and likely involves activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signalling pathways.