News & Events


Regulation Of Heart Channel Proteins Via Stress Signaling

Thursday, January 23, 2020 - 18:30 to 19:30
Dr. Omid Haji-Ghassemi
Department of Biochemistry & Molecular Biology, The University of British Columbia
Event Category: 
CBDG - Chemical Biology Discussion Group
Chemistry D300


A key component of all muscle contraction is the entry of calcium ions into muscle cells. Thus, having the right amount of calcium at the right time is critical. When we experience stress our hearts pump faster, and whole bunch of stress signaling happens in our heart muscle cells. This typically involves stimulation of the beta-adrenergic pathway which leads to the subsequent activation of cAMP-dependent protein kinase A (PKA). PKA has thus been proposed to regulate calcium entry into cardiomyocytes during stress signaling via the L-type calcium channel (CaV1.2) and the ryanodine receptor 2 (RyR2). Ryanodine Receptors (RyR) are huge intracellular ion channels, located in the sarcoplasmic and endoplasmic reticulum, where they control the release of stored calcium ions whereas CaV1.2 channel is located on the plasma membrane. Both channels are targeted by disease-causing mutations and are under strict regulation by auxiliary proteins, small molecules, and post-translational modifications (PTMs). PTMs of these channels is a cornerstone of their physiological and pathophysiological regulation; and aberrant phosphorylation has been implicated in a multitude of disorders ranging from heart failure to Alzheimer’s disease.

Despite decades of research, the molecular mechanism underlying this modulation is enigmatic with multiple sites being implicated. Further there is some controversy regarding which sites are being phosphorylated by PKA and which are important for beta-adrenergic responses. Using high-resolution crystal structures, we show how PKA engages both the RyR2 and CaV1.2 channels in conjunction with kinase assays, highlighting the sites that are preferentially phosphorylated by PKA. We recently determined how the phosphorylation hot spot domain of RyR2 engages PKA by wrapping around the large-lobe of its catalytic subunit, resulting in an extensive interface not seen in PKA complexes with isolated peptides. We also trapped complexes in both closed and open forms of the PKA catalytic subunit, showing that the RyR2 substrate can already bind prior to closing of PKA. The interface is targeted by multiple disease-associated mutations that can affect the interaction and catalytic activity. Finally, we found when one site is phosphorylated in RyR2, another site is more likely to be phosphorylated by PKA, which can lead to amplification of the stress signal.