Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 216

provokes a conformational change that removes the C-terminal auto-inhibitory tail,
thereby allowing access to the ATP-binding site and simultaneously relieving auto-
inhibition by partial unfolding that stimulates the kinase domain for subsequent
autophosphorylation [ 376 ].
Titin is responsible for myocyte elasticity by acting as a spring for sarcomere
retraction of stretched cardiomyocytes. Titin near-Z-disc and near-M-line segments
bind to actin and myosin and myosin-binding protein-C MyBPc3, respectively.
In the relaxed state, titin I-band segment is highly folded [ 377 ]. When the sarcomere
is stretched, titin extensible I-band segment elongates and develops a tension.
During contraction below slack length, myosin filaments move into the near-Z-disc
segment of titin that then generates a restoring force useful for diastolic filling. Titin
I-band segment is composed of many subsegments of different rheological proper-
ties. Among these subsegments, N2a and spring element N2b in the cardiomyocyte
sarcomere determine titin isoforms (N2b and N2ba). Titin subtype N2ba contains
both N2a and N2b segments. Cardiomyocytes coexpress long (N2ba) and short
(N2b) titin isoforms in half-sarcomeres. The N2ba-to-N2b ratio changes to adjust
stiffness. 39 The A-band and near-Z-disc segments are inextensible.
Titin N2b subsegment interacts with members of the LIM family that bind
creatine kinase and adenylate cyclase for appropriate compartmentation. Titin
N2b subsegment is a substrate for protein kinase-A [ 378 ]. Ventricular stiffness may
then be modulated by adrenergic signaling via titin phosphorylation.
Calcium binding to titin, especially to N2ba, also affects the titin rheology.
Calcium also alters interactions between titin and actin. Ca 2 + -binding protein
S100A1 that exists in high concentration in the myocardium inhibits the interaction
between titin and actin.

5.3.5.3 Telethonin

Titin crosses the Z disc up to its binding partner telethonin , or titin-cap (T-cap), at
the periphery of the adjacent Z disc. Telethonin links titin to signaling and structural
molecules, such as delayed rectifier K + channel in the T tubule and small ankyrin-1
that couples the T tubule to the sarcoplasmic reticulum. Titin also binds obscurin
that associates with ankyrin.
Interactions between the Z-disc segment and various compounds may act in the
positioning of the sarcoplasmic reticulum and T tubule close to the I band and ensure
structure mobility according to sarcomere activity.

39 The N2ba distribution depends on the cardiac wall region (atria express more N2ba than
ventricles), apicobasal location, and transmural layer within the ventricular myocardium. Titin
subsegment isoform N2ba is less extensible than N2b subsegment.