Title: Cardiac T-Tubule Microanatomy and Function | Physiological Reviews
Headings: Cardiac T-Tubule Microanatomy and Function
Cardiac T-Tubule Microanatomy and Function
Abstract
I. INTRODUCTION
II. CARDIAC T-TUBULE STRUCTURE
A. History of T-Tubule Structure-Related Research
B. Gross Morphology and Geometry
C. Membrane Ultrastructure and Microdomains
1. cBIN1 microfolds: microdomains supporting LTCC-RyR dyads
2. Caveoli (caveolae): β-AR/LTCC signaling hubs
3. Ankyrin B microdomains: NCX/NKA/InsP 3 macromolecular complex
D. Peri-Membrane Cytoskeleton Scaffolds at Cardiac T-Tubules
1. Actin filaments, tropomyosin, and N-WASP
2. Costamere complex and t-tubule membrane-associated scaffolds
3. Myofilament structural proteins
E. Variation in Cardiac T-Tubule Geometry
III. TRANSMEMBRANE PROTEINS AT CARDIAC T-TUBULES
A. Ion Handling Proteins (Channels/Transporters/Pumps)
1. Ca 2+ handling proteins
2. Na + handling proteins
3. K + handling proteins
B. Signaling Molecules at Cardiac T-Tubules
IV. FUNCTION OF CARDIAC T-TUBULES
A. Dyad and EC Coupling
1. LTCC trafficking and clustering to dyads through BIN1
2. RyR recruitment to dyads through BIN1
3. Junctophilin-2 in t-tubule-jSR junctional membrane complex formation
B. Ion Diffusion and Membrane Excitability
C. Other Microdomain-Related Functions
V. LIFE CYCLE OF CARDIAC T-TUBULES
A. Membrane Biogenesis, Maintenance, and Turnover
B. Ion Channel Trafficking and Half-Life
VI. ALTERATION OF T-TUBULE STRUCTURE AND FUNCTION IN HEART FAILURE
VII. CONCLUSIONS
GRANTS
DISCLOSURES
Acknowledgments

Content: Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts. I. INTRODUCTION
Cardiac transverse tubules (t-tubules) are highly branched invaginations of cardiomyocyte sarcolemma that are rich in ion channels important for excitation-contraction (EC) coupling, maintenance of resting membrane potential, action potential initiation and regulation, and signaling transduction. Specific to striated muscle cells, t-tubules are invaginations of the sarcolemma, penetrating into the intracellular space of myocytes. These tubular invaginations form a complex network with transverse tubules that are interconnected within the cytoplasm by longitudinal tubules.