73Despite the seemingly equal contribution of these IP 3 R isoforms to form the
IP 3 R/Ca2+ channels, there is relatively little sequence homology between the iso-
forms with the exception of the L3-2 loop that maintains well conserved amino acid
sequences throughout the different isoforms across species. The sequence compari-
son of the L3-2 regions of the IP 3 Rs among the isoforms and different species is
shown in Table 2. Assuming the substitutions in amino acids of similar property as
conserved, the degree of conservation reaches ~75%, even including the nematode.
In line with its potential importance in the function of IP 3 Rs, the L3-2 loop of the
IP 3 R has been shown to participate in the interaction with chromogranins (Yoo and
Lewis 1994 , 1995 , 1998 , 2000 ). Underscoring such a structural fit between chromo-
granins and the IP 3 Rs, a near-atomic level structure of the IP 3 R1 that was resolved
by cryo-electron microscopy has indeed revealed the protruding intraluminal L3-2
loops in its tetrameric form (Fan et al. 2015 ).
3 CGA and CGB Sequence Comparison
There are two conserved regions not only among the same type of chromogranins
from different species but also among the different types of chromogranins from a
wide variety of species; one being the near N-terminal region, usually amino acid
residues number 20–40, and the other being the 23–25 amino acids from the
C-terminal end (Bartolomucci et al. 2011 ; Helle 2000 ; Montero-Hadjadje et al.
2008 ; Taupenot et al. 2003 ; Winkler and Fischer-Colbrie 1992 ). As shown in
sequence comparison (Table 1 ), the near N-terminal region of chromogranins A and
B is highly conserved, strongly implicating potentially important roles of this region
in the function of chromogranins. Interestingly, the conserved near N-terminal
region is boxed between two cysteine residues that are invariably present in this
region of chromogranins A and B across species.
As if to explain the reasons for the high degree of sequence conservation, the
conserved near N-terminal region of chromogranins has been shown to specifically
interact with the L3-2 loop of the IP 3 Rs (see below). This fact further underscored
the possibility of the critical role of the near N-terminal region in the function of
chromogranins. Accordingly, the conserved near N-terminal region of chromogra-
nins has indeed been shown to be indispensable in targeting chromogranins to
secretory granules (Courel et al. 2006 ; Glombik et al. 1999 ; Kang and Yoo 1997 ;
Taupenot et al. 2002 ; Yoo and Kang 1997 ; Thiele and Huttner 1998 ; Montero-
Hadjadje et al. 2009 ; Yoo et al. 2014 ), i.e., chromogranin fragments without the near
N-terminal region failed to localize in secretory granules and were shown to be
constitutively secreted. Moreover, the conserved C-terminal regions of chromogra-
nins A and B participate in dimerization and tetramerization of chromogranins
(Thiele and Huttner 1998 ; Yoo and Lewis 1992 , 1993 , 1996 ): CGA forms homodi-
mer at pH 7.5 and homotetramer at pH 5.5, but in the presence of CGB, CGA and
CGB form CGA-CGB heterodimer at pH 7.5 and CGA 2 -CGB 2 heterotetramer at
pH 5.5 (Yoo and Lewis 1996 ).
Conserved Nature of the Inositol 1,4,5-Trisphosphate Receptor and Chromogranin...