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primitive species such as protozoa and nematodes that contain only a single IP 3 R
type. These facts amply suggest that the coupling and activation of the IP 3 R/Ca2+
channels by chromogranins has a very fundamental significance and a deep-rooted
origin in the intracellular Ca2+ signaling systems in the biokingdom.
In particular, the ability of CGB to bind and activate the IP 3 R/Ca2+ channels at
both acidic and physiological pH appears to underscore the critical importance of
the IP 3 R/Ca2+ channel modulatory role of CGB in secretory cells, encompassing
both the cytoplasm in form of secretory granules and the ER, and the nucleus in the
form of IP 3 -sensitive nucleoplasmic Ca2+ store vesicles. Hence, the molecular basis
of the coupling between the IP 3 Rs and chromogranins, and its role in intracellular
Ca2+ homeostasis of secretory cells are discussed here.
2 IP 3 R Topology
The IP 3 R monomers are composed of ~2800 amino acids with six transmembrane
domains near the C-terminal end (Fig. 1 ). There are three IP 3 R types, types 1, 2, and
3, and a complex of homo- and/or heterotetramers of these isoforms forms a Ca2+
channel (Foskett et al. 2007 ; Fan et al. 2015 ). The six transmembrane domains of
the IP 3 Rs are located in amino acid residues number 2500–2700, which form three
intraluminal loops, but the third loop is made of two half-loops due to a partial
burial of the middle region of this loop in the membrane (Fig. 1 ). As a result, the
loops are termed L1, L2, and L3-1 and L3-2.
Table 2 Conserved amino acid sequences of the chromogranin-interacting intraluminal loop L3-2
of the IP 3 receptors across species
aThe numbers shown indicate the position of the amino acids in each IP 3 receptor and the colors
denote identical (red), conserved (blue), and different (black) residues
S. H. Yo o