Key result
Transgenic mice expressing mutated α 1C subunits showed that acute β-adrenergic regulation of Ca V 1.2 requires neither conserved Ser/Thr phosphorylation nor C-terminal proteolytic cleavage.
Acute β-adrenergic regulation of the cardiac L-type calcium channel does not require PKA phosphorylation of conserved Ser/Thr sites or C-terminal proteolytic cleavage of the α1C subunit.
Challenges models of CaV1.2 β-adrenergic regulation via phosphorylation or cleavage; leaves open the mechanism in human hearts.
Significance Calcium influx through the cardiac voltage-dependent L-type calcium channel (Ca V 1.2) increases during “fight or flight” through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. None of the previously identified sites in the α 1C subunit, each painstakingly and singly investigated, were shown to be required for adrenergic modulation of Ca V 1.2. Our approach allowed an unprecedented and massive increase in throughput, because we mutated many potential PKA phosphorylation sites throughout α 1C . By creating transgenic mice expressing either α 1C with alanines substituted for all conserved consensus PKA phosphorylation sites or, separately, α 1C without C-terminal proteolytic cleavage, our paradigm-shifting results show that acute β-adrenergic regulation of Ca V 1.2 does not require phosphorylation of any conserved Ser/Thr of α 1C or the proteolytic cleavage of the C terminus of α 1C .
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Katchman et al. (2017) studied this question. Transgenic mutation of α 1C subunit (alanine substitutions or no C-terminal cleavage) was evaluated on Acute β-adrenergic regulation of Ca V 1.2. Transgenic mice expressing mutated α 1C subunits showed that acute β-adrenergic regulation of Ca V 1.2 requires neither conserved Ser/Thr phosphorylation nor C-terminal proteolytic cleavage.
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