L-type voltage-gated Ca1.2 channels crucially regulate cardiac muscle contraction. Activation of β-adrenergic receptors (β-AR) augments contraction via protein kinase A (PKA)-induced increase of calcium influx through Ca1.2 channels. To date, the full β-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a Ca1.2 inhibitory protein, as essential for PKA regulation of Ca1.2. We corroborated this finding and reconstituted the complete pathway with agonist activation of β1-AR or β2-AR in oocytes. We found, and distinguished between, two distinct pathways of PKA modulation of Ca1.2: Rad dependent (∼80% of total) and Rad independent. The reconstituted system reproduces the known features of β-AR regulation in cardiomyocytes and reveals several aspects: the differential regulation of posttranslationally modified Ca1.2 variants and the distinct features of β1-AR versus β2-AR activity. This system allows for the addressing of central unresolved issues in the β-AR-Ca1.2 cascade and will facilitate the development of therapies for catecholamine-induced cardiac pathologies.
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| http://dx.doi.org/10.1073/pnas.2100021118 | DOI Listing |
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