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: 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. The transverse tubules occur around myofilaments, anchoring to sarcomeric z-discs through costameres. The phospholipid-rich t-tubule lipid bilayers are shaped and maintained by membrane scaffolding proteins and intracellular cytoskeleton, as well as surrounding extracellular matrix. T-tubule membrane contains microdomains that compartmentalize transmembrane ion handling proteins and signaling molecules. Together, t-tubules are effective organelles that serve as a centralized signaling hub controlling cardiac contractile function and electrophysiology. The most recognized function of t-tubules is regulation of cardiac EC coupling by concentrating voltage-gated L-type calcium channels (LTCCs) and positioning them in close proximity to calcium sense and release channels, ryanodine receptors (RyRs), at the junctional membrane of sarcoplasmic reticulum (jSR).