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1 Introduction
Secretory granules from a wide variety of secretory cells, ranging from primitive
unicellular organisms to humans, serve as the major IP 3 -sensitive intracellular Ca2+
store (Yoo 2010 , 2011 ). The main reason secretory granules can function as the
major IP 3 -sensitive intracellular Ca2+ store is the abundant presence of the IP 3 R/Ca2+
channels and the high capacity, low affinity Ca2+ storage proteins chromogranins in
secretory granules in addition to 40 mM Ca2+ (Haigh et al. 1989 ; Winkler and
Westhead 1980 ). Secretory granules contain the highest concentrations and the larg-
est amounts of all three IP 3 R types and chromogranins A (CGA) and B (CGB) in
secretory cells (Huh et al. 2005b, 2005c). A significant portion of cellular contents
of these molecules is also contained in the endoplasmic reticulum (ER) and the
nucleus with the exception of CGA which is absent in the nucleus (Yoo et al. 2002 ).
As if to highlight the physiological significance of colocalization of these mole-
cules in the same organelles, chromogranins A and B directly interact with the IP 3 R/
Ca2+ channels (Yoo et al. 2001 ) and activate the channels; increasing the open proba-
bility 8- to 16-fold and the mean open time 9- to 42-fold, respectively (Thrower et al.
2002 , 2003 ; Yoo and Jeon 2000 ). Yet, the interaction properties of chromogranins with
the IP 3 Rs differ depending on the pH milieu: chromogranin A binds and activates the
IP 3 R/Ca2+ channels only at intragranular pH 5.5, dissociating from each other and
becoming ineffective at near physiological pH 7.5, in contrast to chromogranin B that
stays coupled to and activates the IP 3 R/Ca2+ channels at both the intragranular pH 5.5
and the near physiological pH 7.5 (Thrower et al. 2003 ; Yoo et al. 2000 ).
Moreover, being the first example of granin proteins existing outside of secretory
granules chromogranin B has further been shown to localize in the nucleus, along
with all three IP 3 R types (Yoo et al. 2005 ; Huh and Yoo 2003 ); chromogranin B and
the IP 3 Rs colocalize in numerous small nucleoplasmic Ca2+ store vesicles (Huh
et al. 2006b; Yoo et al. 2005 , 2014 ). Although the normal physiological pH of cells
is ~7.4, including that of the nucleus and endoplasmic reticulum (ER), secretory
granules maintain an acidic pH 5.5, thus providing a different environment for the
chromogranin-IP 3 R/Ca2+ channel interaction and function. This pH-dependence of
chromogranin-IP 3 R interaction and different localization of chromogranins A and B
in subcellular organelles appear to reflect the differences each chromogranin con-
tributes to the overall Ca2+ homeostasis in secretory cells.
In spite of the apparent differences in each chromogranin’s role in intracellular
Ca2+ homeostasis, there lies an invariable common molecular organization in the
cooperative works between the IP 3 Rs and chromogranins that the IP 3 R/Ca2+ channel
modulatory role of chromogranins is through the interaction between the highly
conserved near amino (N)-terminal regions of chromogranins A and B (Table 1 )
(Helle 2000 ; Montero-Hadjadje et al. 2008 ; Taupenot et al. 2003 ; Winkler and
Fischer-Colbrie 1992 ; Bartolomucci et al. 2011 ) and the equally well conserved
intraluminal L3-2 loops of the IP 3 Rs (Fig. 1 and Table 2 ). The near N-terminal
region of chromogranins is conserved not only between chromogranins A and B but
also across different species. Similarly, the L3-2 loop of the IP 3 Rs is also well con-
served not only between the three types but also across different species, including
S. H. Yo o