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: 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). The closely approximated LTCCs and RyRs form calcium releasing units, dyads, where calcium transients are initiated following each beat-to-beat action potential. With recent advances in high-resolution imaging technologies, detailed t-tubule microdomain structural organization and newly recognized functions are starting to emerge. For instance, the t-tubular invagination is not smooth, but consists of extensive membrane microfolds sculpted by a cardiac isoform of a BAR domain containing protein bridging integrator 1 (BIN1 or amphiphysin 2) ( 91 ). Cardiac BIN1 (cBIN1) organized membrane microfolds generate diffusion barriers which slow t-tubule-associated extracellular ionic diffusion, preserving electrical stability of myocytes during tachycardia-related fluctuations of ionic concentrations in the local extracellular and possibly intracellular environment ( 91 ). In addition, cBIN1-microfolds also organize local microdomains for efficient and dynamic regulation of cardiac dyad function, regulating EC coupling ( 66, 93, 94 ).