79magnitude of IP 3 -mediated nucleoplasmic Ca2+ releases (Fig. 4B). Although CGA
expression in nonsecretory NIH3T3 cells was without any effect on the IP 3 -induced
Ca2+ release in the nucleus, CGB expression in NIH3T3 cells increased the IP 3 -
induced Ca2+ release in the nucleus ~315% (Fig. 4B) (Huh et al. 2006a), thereby
demonstrating the crucial role of CGB in the nuclear Ca2+ control.
Nonsecretory cells that do not contain chromogranins would not need as subtle and
diverse Ca2+ control machineries as secretory cells, and for that matter, the nonsecre-
tory cells would be able to meet their cellular Ca2+ control needs without the service
of multi-functional molecules such as chromogranins. Instead, the roles played by
chromogranins in secretory cells will probably be met by other molecules that are
functionally equivalent to chromogranins, and these molecules might as well exist in
the IP 3 -sensitive nucleoplasmic Ca2+ store vesicles of nonsecretory cells as CGB exists
inside the small IP 3 -sensitive nucleoplasmic Ca2+ store vesicles of secretory cells.
8 Conclusion
Direct coupling between the two ancient family of proteins chromogranins and the
IP 3 Rs, via the interaction between the near N-terminal regions of chromogranins
and the L3-2 loops of the IP 3 Rs, is likely to have served as the beginning of IP 3 -
dependent intracellular Ca2+ signaling systems in the biokingdom. In view of the
requirements of the existence of signaling molecules, i.e., Ca2+ and IP 3 , and of the
molecules that interact with them in order for the Ca2+ signaling systems to operate,
the conserved nature of the coupling between the Ca2+ storage proteins chromogra-
nins and the IP 3 R/Ca2+ channels appears to testify a very ancient origin of the emer-
gence of the IP 3 -dependent Ca2+ signaling systems in organisms. That chromogranins
store Ca2+ and modulate the Ca2+ channels while the IP 3 Rs sense the Ca2+ mobiliza-
tion signal IP 3 and double as the Ca2+ channels in the same organelles seems to lend
a strong support to such a notion. Further, given the highly conserved nature of the
L3-2 loops of the IP 3 Rs even in protozoa and nematodes that have only one type of
IP 3 R, it appears inevitable that some type of Ca2+ storage and Ca2+ channel-
modulatory proteins that are functionally equivalent to chromogranins of secretory
cells also widely exist in a variety of nonsecretory cells across the biokingdom.
Acknowledgement The author thanks Yong Suk Hur for help in preparing the manuscript.
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