Cardiac Ca2+signaling:history，current advances and future challenge

Masao ENDOH

(Yamagata University School of Medicine，Yamagata 990 －9585，Japan)

It is currently clarified that Ca2+ions play a key role not only in cardiac E－C coupling in contractile regulation，but also in regulation of SA node pace－making activity，genetic regulation and other important processes，including intracellular signal transduction，mitochondrial function and cell death.Contractile regulation is achieved by two mechanisms，the regulation of Ca2+transients and/ormyofilament Ca2+sensitivity.The cardiac E －C coupling is classified into three processes based on the role of Ca2+in the regulation.Ca2+binding to troponin C located in the center of E－C coupling is termed central mechanism，regulation of Ca2+transients is termed upstream mechanism，and the modulation of the process subsequent to troponin C－Ca2+binding is termed downstream mechanism.

These mechanisms were defined first in 1978 when Allen and Blinks succeeded in detecting Ca2+transients by means of microinjection of the Ca2+－sensitive bioluminescent protein aequorin extracted from Aequorea folskalea or Aequorea aequorea simultaneously with contraction of frog ventricular muscle.Representative regulation of the upstream mechanism is achieved by elevation of extracellular Ca2+concentration，force－frequency relationship and β－adrenoceptor stimulation.On the other hand，an increase in myofilament Ca2+sensitivity is induced by Frank－Starling's law，β－stimulation，GPCR－NE crosstalk with ET－1 and Ca2+sensitizers，while a decrease occurring in acidosis.

The characteristics of the role of Ca2+in regulation of the SA node pace－making activity have been elucidated in the laboratory of Edward Lakatta and his co－workers in Baltimore.The SA node pace－making activity is regulated by mutual cooperation of M clock，membrane clock operative with membrane potential and current，and Ca2+clock determined by local Ca2+release from RYR in SR.

Pieces of experimental evidence identifying a definite role of Ca2+in genetic regulation have currently been obtained.TRP channels are Ca2+－permeable cation channels，28 TRP－related genes have been cloned，and they are grouped into 6 families.TRP channels are able to activate store－operated channels(SOCs)，acting as the sensor of various cellular functions.Among them，TRPC channels have been shown to play a crucial role in induction of the cardiac hypertrophy and heart failure.Temporal and spatial segregation may explain partially the differential regulation:temporal segregation can be achieved by systolic Ca2+transients for inotrope and diastolic Ca2+release for chronotrope;fast and transient in systolic Ca2+transients and slow and continuous in genetic regulation.Spatial segregation can be achieved by regional Ca2+elevation in sub－sarcolemmal microdomain for genetic regulation and global Ca2+elevation for contractile regulation.Functional regulation is mainly supported by Ca2+release from RyR，while genetic regulation，by TRPC channels，IP3receptors，and SOCs.

However，pieces of evidence are still fragmentary and further development of novel experimental procedures to specifically detect Ca2+in microdomains will be necessary to get compelling evidence for differential role of Ca2+in cardiac contractile and genetic regulation in more details in the future.