S100A1: a regulator of striated muscle sarcoplasmic reticulum Ca2+ handling, sarcomeric, and mitochondrial function

Abstract

Calcium (Ca(2+)) signaling plays a key role in a wide range of physiological functions including control of cardiac and skeletal muscle performance. To assure a precise coordination of both temporally and spatially transduction of intracellular Ca(2+) oscillations to downstream signaling networks and target operations, Ca(2+) cycling regulation in muscle tissue is conducted by a plethora of diverse molecules. Ca(2+) S100A1 is a member of the Ca(2+)-binding S100 protein family and represents the most abundant S100 isoform in cardiac and skeletal muscle. Early studies revealed distinct expression patterns of S100A1 in healthy and diseased cardiac tissue from animal models and humans. Further elaborate investigations uncovered S100A1 protein as a basic requirement for striated muscle Ca(2+) handling integrity. S100A1 is a critical regulator of cardiomyocyte Ca(2+) cycling and contractile performance. S100A1-mediated inotropy unfolds independent and on top of beta AR-stimulated contractility with unchanged beta AR downstream signaling. S100A1 has further been detected at different sites within the cardiac sarcomere indicating potential roles in myofilament function. More recently, a study reported a mitochondrial location of S100A1 in cardiomyocytes. Additionally, normalizing the level of S100A1 protein by means of viral cardiac gene transfer in animal heart failure models resulted in a disrupted progression towards cardiac failure and enhanced survival. This brief review is confined to the physiological and pathophysiological relevance of S100A1 in cardiac and skeletal muscle Ca(2+) handling with a particular focus on its potential as a molecular target for future therapeutic interventions.

Figure 1

Schematic depiction of the secondary structure of an S100 protein. The monomeric structure consists of a repetitive EF-hand motif, whereas eachCa²⁺-binding Loop (Loop I and II) is flanked by α-helices. The N-terminal and the C-terminal EF hands are connected by a linker region (hinge region). The hinge region and the C-terminal extension (boxed in red) display the least amount of sequence homology among S100 paralogs. Reproduced with modifications from Donato [5]. [http://www.ncbi.nlm.nih.gov/pubmed/11390274?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=9].

Figure 2

The three-dimensional structure of S100A1 as determined by NMR spectroscopy. (a) S100A1 in the apo state: S100A1 is composed of two identical subunits connected by a linker region (hinge region). Dimerization occurs in an antiparallel manner. (b) S100A1 in the Ca²⁺ bound state: Ca²⁺ binding to both the N- and C-terminal motif results in an altered orientation of H3/4 and the hinge region uncovering hydrophobic residues for the interaction with target molecules. S100A1 residues 75–94 are indicated by the red box. Reproduced with modifications from Wright et al. [7].

Figure 3

Proposed model for S100A1 inotropic actions in cardiomyocytes. (a) During excitation-contraction coupling, the action potential-dependent opening of the L-type Ca²⁺ channel (LTCC) results in a transsarcolemmal Ca²⁺ entry which triggers sarcoplasmic reticulum (SR) Ca²⁺ release via Ryanodine Receptor 2 (RyR2) that in turn activates myofilament cross-bridge cycling and mechanical contraction. During diastole, the SR Ca²⁺ reuptake is conducted by the SR Ca²⁺ ATPase (SERCA), whereas the sodium-calcium exchanger (NCX) extrudes Ca²⁺ from the cardiomyocyte to keep steady-state conditions. (b) S100A1 interacts with both RyR2 and the SERCA-Phospholamban (PLB)-complex and is present at myofilaments and mitochondria. Increased S100A1 protein levels result in an enhanced systolic SR Ca²⁺ release via RyR2 without influencing LTCC activity. Augmented SR Ca²⁺ release is balanced by an intensified SERCA activity leading to an improved Ca²⁺ cycling and a raised force generation. Additionally, the S100A1/F1-ATPase interference in mitochondria is associated with an enhanced generation of cytoplasmic ATP in cardiomyocytes. Moreover, S100A1 inhibits the actin-titin interactions in the sarcomere, resulting in a reduced precontractile passive tension [24].