Neuroendocrine secretory protein 7B2: structure, expression and functions

Abstract

7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells. Its sequence has been elucidated in many phyla and species. It shows high similarity among mammals. A Pro-Pro-Asn-Pro-Cys-Pro polyproline motif is its most conserved feature, being carried by both vertebrate and invertebrate sequences. It is biosynthesized as a precursor protein that is cleaved into an N-terminal fragment and a C-terminal peptide. In neuroendocrine cells, 7B2 functions as a specific chaperone for the proprotein convertase (PC) 2. Through the sequence around its Pro-Pro-Asn-Pro-Cys-Pro motif, it binds to an inactive proPC2 and facilitates its transport from the endoplasmic reticulum to later compartments of the secretory pathway where the zymogen is proteolytically matured and activated. Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo. The PC2–7B2 model defines a new neuroendocrine paradigm whereby proteolytic activation of prohormones and proneuropeptides in the secretory pathway is spatially and temporally regulated by the dynamics of interactions between converting enzymes and their binding proteins. Interestingly, unlike PC2-null mice, which are viable, 7B2-null mutants die early in life from Cushing's disease due to corticotropin (‘ACTH’) hypersecretion by the neurointermediate lobe, suggesting a possible involvement of 7B2 in secretory granule formation and in secretion regulation. The mechanism of this regulation is yet to be elucidated. 7B2has been shown to be a good marker of several neuroendocrine cell dysfunctions in humans. The possibility that anomalies in its structure and expression could be aetiological causes of some of these dysfunctions warrants investigation.

Evolutionary principles underlying neuron subtype encoding and diversification in animals

“…The putative neuronal clusters show increased expression of dozens of genes with well-characterized core neuronal functions in other species ( Figure 1E , Supplemental Table 3 ). Specifically, marker genes shared amongst most or all of our putative neuron clusters include components of synaptic vesicles and the cytomatrix at the presynaptic active zone ( syt1/2/5, vamp1/2/3 (synaptobrevin), pclo2, snap23/25, syde1/2, syn, syt4/11, cadps (caps1), cplx1/2 , stxbp5 ( tomosyn )) (Burkhardt and Sprecher 2017; Wentzel et al 2013; Wolfes and Dean 2020; Gundelfinger et al 2016; Fujita et al 1998); genes associated with dense-core vesicles ( scg5 (7b2), ia2 (ptprn) ) (Cai et al 2011; Harashima et al 2005; Stojilkovic et al 2025; MBIKAY et al 2001); components or regulators of the axon cytoskeleton ( kif1, kif5, fez1/2 (unc-76), mapt (tau) , the map1a/b/s paralog map1a, dclk1/2 , the faxc paralog fax1 , robo1/2/3 ) (Okada et al 1995; Campbell et al 2014; Bloom and Horvitz 1997; Gindhart et al 2003; Nawabi et al 2015; Hill et al 1995; Gonda et al 2020; Cario and Berger 2023); genes involved in scaffolding the synapse at the pre- or post-synaptic membrane ( maguk, nrcam/l1cam-like, ncam, nlgn ) (Giagtzoglou et al 2009; Liebeskind et al 2017; Zhu et al 2016; Sakurai 2012); the voltage-gated calcium channel cacna1 (Szymanowicz et al 2024); the ion channel interacting gene stomatin ( stom ) (Lapatsina et al 2012); and several TFs, including myt1/2/3 (orthologous to vertebrate myt1 , myt1l ( myt2 ), and st18 ( myt3 )), which has a conserved role in repressing non-neuronal gene programs (J. Lee et al 2019; Mall et al 2017), and nr4a and camta , unrelated TFs which all play roles in activity-dependent transcriptional regulation (Bas-Orth et al 2016; Hawk and Abel 2011), confirming that these cells do indeed have a neuronal identity.…”

Evolutionary principles underlying neuron subtype encoding and diversification in animals

“…The putative neuronal clusters show increased expression of dozens of genes with well-characterized core neuronal functions in other species ( Figure 1E , Supplemental Table 3 ). Specifically, marker genes shared amongst most or all of our putative neuron clusters include components of synaptic vesicles and the cytomatrix at the presynaptic active zone ( syt1/2/5, vamp1/2/3 (synaptobrevin), pclo2, snap23/25, syde1/2, syn, syt4/11, cadps (caps1), cplx1/2 , stxbp5 ( tomosyn )) (Burkhardt and Sprecher 2017; Wentzel et al 2013; Wolfes and Dean 2020; Gundelfinger et al 2016; Fujita et al 1998); genes associated with dense-core vesicles ( scg5 (7b2), ia2 (ptprn) ) (Cai et al 2011; Harashima et al 2005; Stojilkovic et al 2025; MBIKAY et al 2001); components or regulators of the axon cytoskeleton ( kif1, kif5, fez1/2 (unc-76), mapt (tau) , the map1a/b/s paralog map1a, dclk1/2 , the faxc paralog fax1 , robo1/2/3 ) (Okada et al 1995; Campbell et al 2014; Bloom and Horvitz 1997; Gindhart et al 2003; Nawabi et al 2015; Hill et al 1995; Gonda et al 2020; Cario and Berger 2023); genes involved in scaffolding the synapse at the pre- or post-synaptic membrane ( maguk, nrcam/l1cam-like, ncam, nlgn ) (Giagtzoglou et al 2009; Liebeskind et al 2017; Zhu et al 2016; Sakurai 2012); the voltage-gated calcium channel cacna1 (Szymanowicz et al 2024); the ion channel interacting gene stomatin ( stom ) (Lapatsina et al 2012); and several TFs, including myt1/2/3 (orthologous to vertebrate myt1 , myt1l ( myt2 ), and st18 ( myt3 )), which has a conserved role in repressing non-neuronal gene programs (J. Lee et al 2019; Mall et al 2017), and nr4a and camta , unrelated TFs which all play roles in activity-dependent transcriptional regulation (Bas-Orth et al 2016; Hawk and Abel 2011), confirming that these cells do indeed have a neuronal identity.…”

The monoaminergic system in a bivalve larva: temporal deployment and spatial organization

“…The larval neurosecretory system of the Mediterranean mussel was characterized from Late Gastrulae to D-Veligers by double in situ HCR with Secretogranin V ( 7b2 ), a neuroendocrine protein detected in the secretory neurons of both deuterostomes and protostomes (68, 69) (Fig. 3A and B).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, tachykinin receptor was the only detectable neuropeptide/neuropeptide receptor identified in our EE populations ( Figure 2B ). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (26,27) and Syt1, and showed expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figure 2B) (14,28). Interestingly, the EE population showed strong enrichment for NEUROD6, a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals ( Figure 2B) (29).…”

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population (Supplemental Figure 3A). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (33,34) and Syt1, and showed low and nonspecific expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) (Figure 2D, Supplemental Figure 3A) (14,35). Interestingly, the EE population showed strong enrichment for NEUROD6, an ortholog for neurogenic differentiation factor 4 in Aedes aegypti (AAEL004252) and for a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals (Figure 2D, Supplemental Figure 3A) (36).…”

Evolutionary principles underlying neuron subtype encoding and diversification in animals

“…The putative neuronal clusters show increased expression of dozens of genes with well-characterized core neuronal functions in other species ( Figure 1E , Supplemental Table 3 ). Specifically, marker genes shared amongst most or all of our putative neuron clusters include components of synaptic vesicles and the cytomatrix at the presynaptic active zone ( syt1/2/5, vamp1/2/3 (synaptobrevin), pclo2, snap23/25, syde1/2, syn, syt4/11, cadps (caps1), cplx1/2 , stxbp5 ( tomosyn )) (Burkhardt and Sprecher 2017; Wentzel et al 2013; Wolfes and Dean 2020; Gundelfinger et al 2016; Fujita et al 1998); genes associated with dense-core vesicles ( scg5 (7b2), ia2 (ptprn) ) (Cai et al 2011; Harashima et al 2005; Stojilkovic et al 2025; MBIKAY et al 2001); components or regulators of the axon cytoskeleton ( kif1, kif5, fez1/2 (unc-76), mapt (tau) , the map1a/b/s paralog map1a, dclk1/2 , the faxc paralog fax1 , robo1/2/3 ) (Okada et al 1995; Campbell et al 2014; Bloom and Horvitz 1997; Gindhart et al 2003; Nawabi et al 2015; Hill et al 1995; Gonda et al 2020; Cario and Berger 2023); genes involved in scaffolding the synapse at the pre- or post-synaptic membrane ( maguk, nrcam/l1cam-like, ncam, nlgn ) (Giagtzoglou et al 2009; Liebeskind et al 2017; Zhu et al 2016; Sakurai 2012); the voltage-gated calcium channel cacna1 (Szymanowicz et al 2024); the ion channel interacting gene stomatin ( stom ) (Lapatsina et al 2012); and several TFs, including myt1/2/3 (orthologous to vertebrate myt1 , myt1l ( myt2 ), and st18 ( myt3 )), which has a conserved role in repressing non-neuronal gene programs (J. Lee et al 2019; Mall et al 2017), and nr4a and camta , unrelated TFs which all play roles in activity-dependent transcriptional regulation (Bas-Orth et al 2016; Hawk and Abel 2011), confirming that these cells do indeed have a neuronal identity.…”

The monoaminergic system in a bivalve larva: temporal deployment and spatial organization

“…The larval neurosecretory system of the Mediterranean mussel was characterized from Late Gastrulae to D-Veligers by double in situ HCR with Secretogranin V ( 7b2 ), a neuroendocrine protein detected in the secretory neurons of both deuterostomes and protostomes (68, 69) (Fig. 3A and B).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, tachykinin receptor was the only detectable neuropeptide/neuropeptide receptor identified in our EE populations ( Figure 2B ). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (26,27) and Syt1, and showed expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figure 2B) (14,28). Interestingly, the EE population showed strong enrichment for NEUROD6, a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals ( Figure 2B) (29).…”

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population (Supplemental Figure 3A). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (33,34) and Syt1, and showed low and nonspecific expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) (Figure 2D, Supplemental Figure 3A) (14,35). Interestingly, the EE population showed strong enrichment for NEUROD6, an ortholog for neurogenic differentiation factor 4 in Aedes aegypti (AAEL004252) and for a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals (Figure 2D, Supplemental Figure 3A) (36).…”

Evolutionary principles underlying neuron subtype encoding and diversification in animals

“…The putative neuronal clusters show increased expression of dozens of genes with well-characterized core neuronal functions in other species ( Figure 1E , Supplemental Table 3 ). Specifically, marker genes shared amongst most or all of our putative neuron clusters include components of synaptic vesicles and the cytomatrix at the presynaptic active zone ( syt1/2/5, vamp1/2/3 (synaptobrevin), pclo2, snap23/25, syde1/2, syn, syt4/11, cadps (caps1), cplx1/2 , stxbp5 ( tomosyn )) (Burkhardt and Sprecher 2017; Wentzel et al 2013; Wolfes and Dean 2020; Gundelfinger et al 2016; Fujita et al 1998); genes associated with dense-core vesicles ( scg5 (7b2), ia2 (ptprn) ) (Cai et al 2011; Harashima et al 2005; Stojilkovic et al 2025; MBIKAY et al 2001); components or regulators of the axon cytoskeleton ( kif1, kif5, fez1/2 (unc-76), mapt (tau) , the map1a/b/s paralog map1a, dclk1/2 , the faxc paralog fax1 , robo1/2/3 ) (Okada et al 1995; Campbell et al 2014; Bloom and Horvitz 1997; Gindhart et al 2003; Nawabi et al 2015; Hill et al 1995; Gonda et al 2020; Cario and Berger 2023); genes involved in scaffolding the synapse at the pre- or post-synaptic membrane ( maguk, nrcam/l1cam-like, ncam, nlgn ) (Giagtzoglou et al 2009; Liebeskind et al 2017; Zhu et al 2016; Sakurai 2012); the voltage-gated calcium channel cacna1 (Szymanowicz et al 2024); the ion channel interacting gene stomatin ( stom ) (Lapatsina et al 2012); and several TFs, including myt1/2/3 (orthologous to vertebrate myt1 , myt1l ( myt2 ), and st18 ( myt3 )), which has a conserved role in repressing non-neuronal gene programs (J. Lee et al 2019; Mall et al 2017), and nr4a and camta , unrelated TFs which all play roles in activity-dependent transcriptional regulation (Bas-Orth et al 2016; Hawk and Abel 2011), confirming that these cells do indeed have a neuronal identity.…”

The monoaminergic system in a bivalve larva: temporal deployment and spatial organization

“…The larval neurosecretory system of the Mediterranean mussel was characterized from Late Gastrulae to D-Veligers by double in situ HCR with Secretogranin V ( 7b2 ), a neuroendocrine protein detected in the secretory neurons of both deuterostomes and protostomes (68, 69) (Fig. 3A and B).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, tachykinin receptor was the only detectable neuropeptide/neuropeptide receptor identified in our EE populations ( Figure 2B ). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (26,27) and Syt1, and showed expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figure 2B) (14,28). Interestingly, the EE population showed strong enrichment for NEUROD6, a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals ( Figure 2B) (29).…”

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population (Supplemental Figure 3A). The EE population was significantly enriched for canonical neuroendocrine genes (IA2, and SCG5) (33,34) and Syt1, and showed low and nonspecific expression of Syt4, Syt6, Syx1A and nSyb (genes associated with vesicle docking and secretion) (Figure 2D, Supplemental Figure 3A) (14,35). Interestingly, the EE population showed strong enrichment for NEUROD6, an ortholog for neurogenic differentiation factor 4 in Aedes aegypti (AAEL004252) and for a neuronal differentiation gene known to be involved in behavioral reinforcement in mammals (Figure 2D, Supplemental Figure 3A) (36).…”