Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels

Abstract

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers of their intracellular partners the type 2 ryanodine receptors (RyR2) which cluster on the junctional sarcoplasmic reticulum (jSR). The organization and distribution of these two groups of cardiac calcium channel clusters critically underlies the uniform contraction of the myocardium. Ca2+ signaling between these two sets of adjacent clusters produces Ca2+ sparks that in health, cannot escalate into Ca2+ waves because there is sufficient separation of adjacent clusters so that the release of Ca2+ from one RyR2 cluster or supercluster, cannot activate and sustain the release of Ca2+ from neighboring clusters. Instead, thousands of these Ca2+ release units (CRUs) generate near simultaneous Ca2+ sparks across every cardiomyocyte during the action potential when calcium induced calcium release from RyR2 is stimulated by depolarization induced Ca2+ influx through voltage dependent CaV1.2 channel clusters. These sparks summate to generate a global Ca2+ transient that activates the myofilaments and thus the electrical signal of the action potential is transduced into a functional output, myocardial contraction. To generate more, or less contractile force to match the hemodynamic and metabolic demands of the body, the heart responds to β-adrenergic signaling by altering activity of calcium channels to tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests that this tuning process also involves altered expression, and dynamic reorganization of CaV1.2 and RyR2 channels on their respective membranes to control the amplitude of Ca2+ entry, SR Ca2+ release and myocardial function. In heart failure and aging, altered distribution and reorganization of these key Ca2+ signaling proteins occurs alongside architectural remodeling and is thought to contribute to impaired contractile function. In the present review we discuss these latest developments, their implications, and future questions to be addressed.

BIN1 knockdown rescues systolic dysfunction in the aging heart

“…This study provides the first evidence linking age-associated β-AR hypo-responsivity to alterations in Ca 2+ channel clustering and organization. Super-resolution microscopy studies of the nanoscale arrangement of CaV1.2 and RyR2 have fueled the emerging concept that tunable insertion, recycling, and clustering of these channels physiologically during receptor signaling cascades or pathologically in disease, affects Ca 2+ release efficiency and myocardial contractility 7,20,23,24,[60][61][62] . Larger CaV1.2 clusters facilitate enhanced CaV1.2-CaV1.2 physical interactions and cooperative gating that amplifies ICa 20,21,63 while larger RyR2 clusters favor enhanced Ca 2+ spark frequency 25 and larger Ca 2+ transients.…”

“…Nanoscale redistribution and augmentation of cardiac Ca 2+ channel clustering in response to β -AR stimulation also extends to RyR2. Accordingly, acute treatment with the β AR-agonist isoproterenol (ISO) or a phosphorylation-inducing cocktail promotes enhanced RyR2 cluster sizes 22, 23 , as recently reviewed 24 . This dynamic redistribution of RyR2 into larger clusters is orchestrated by the membrane curvature-forming protein bridging integrator 1 (BIN1) 22 and is linked to increased Ca 2+ spark frequency which summate to produce larger Ca 2+ transients 23, 25 .…”

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

“…To this point, we have discussed how Ca V 1.2 channels traffic and form clusters, but what about the other side of the dyad—the jSR? The jSR is a complex structure whose architecture, function, and stability reflect the contribution of several proteins ( Dixon, 2022 ; Jones et al, 2018 ). One of these proteins, junctophilin-2 (JPH2), is anchored to the jSR via its C-terminus and contacts the sarcolemma through lipid-interacting motifs in its N-terminus ( Garbino and Wehrens, 2010 ; Lehnart and Wehrens, 2022 ; Pritchard et al, 2019 ).…”

Spatiotemporal Control of Vascular Ca V 1.2 by α1 C S1928 Phosphorylation

“…4 Emerging evidence suggests that Ca V 1.2 cooperativity can be stimulated by protein kinases. 3,4,15 These results lead to the hypotheses that α1 C subunits may form clusters that facilitate functional α1 C interactions and that phosphorylation of α1 C could be a key initial step inducing and promoting α1 C clustering and Ca V 1.2 cooperative gating. Our study is designed to test these possibilities.…”