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Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications.

Marzagalli R, Scuderi S, Drago F, Waschek JA, Castorina A - Int J Endocrinol (2015)

Bottom Line: Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available.In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state.Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.

View Article: PubMed Central - PubMed

Affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.

ABSTRACT
Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available. In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state. Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.

No MeSH data available.


Related in: MedlinePlus

2D chemical structure of full-length PACAP38 (CID 44566111). The chemical structure was retrieved using the publicly available PubChem database source, accessible at https://pubchem.ncbi.nlm.nih.gov/compound/44566111#.
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fig1: 2D chemical structure of full-length PACAP38 (CID 44566111). The chemical structure was retrieved using the publicly available PubChem database source, accessible at https://pubchem.ncbi.nlm.nih.gov/compound/44566111#.

Mentions: PACAP (molecular formula C203H331N63O53S; for details on PACAP38 chemical structure please refer to Figure 1) was originally isolated from an ovine hypothalamus extract [8]. Two PACAP isoforms have been identified, a 38-amino-acid form (PACAP38) and a C-terminally truncated 27-amino-acid form (PACAP27). It belongs to the secretine, glucagon, and peptide histidine-isoleucine (PHI) superfamily and binds to an overlapping group of receptors. PACAP receptors are G protein-coupled receptors and can be classified into two main groups, PAC1 and VPAC (including VPAC1 and VPAC2 subtypes), both of which activate adenylate cyclase with consequent stimulation of cAMP production and IP accumulation [9, 10]. In distinct cell types, PACAP is able to trigger different pathways, depending on which receptor splice variants are expressed, peptide concentration being used, and other biological factors. Among PACAP functions, the one that mostly emerges is its strong cytoprotective role, promoting survival in many types of neuronal and nonneuronal cells and tissues, including lymphocytes, chondrocytes, endothelial cells, Schwann cells, liver, lung, and ovary [11–17]. In vitro and in vivo studies have shown that the peptide acts through the PAC1 receptors to stimulate various downstream executors of the protein kinase A and C (PKA and PKC) pathways [18–21]. It also activates ion channels, β-arrestin signalling, and mitogen-activated protein (MAP) kinase in some tissues [22, 23]. PACAP and its receptors have been detected in multiple organs, with the highest levels in endocrine glands and in the central nervous system. Lower expression has been identified in gastrointestinal, respiratory, cardiovascular, and urogenital systems [24, 25]. Ultrastructural studies have also revealed that PACAP immunoreactivity is mainly localized near the plasma membrane, in the rough endoplasmic reticulum, in the Golgi's apparatus, and in the cytoplasmic matrix [26–28]. Such a broad distribution of PACAP in several tissues/organs, together with the variety of signalling pathways shown to be activated, poses the peptide in a position suitable to be considered a key drug candidate with the potential to ameliorate a wide spectrum of disorders, including diabetes and its major complications.


Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications.

Marzagalli R, Scuderi S, Drago F, Waschek JA, Castorina A - Int J Endocrinol (2015)

2D chemical structure of full-length PACAP38 (CID 44566111). The chemical structure was retrieved using the publicly available PubChem database source, accessible at https://pubchem.ncbi.nlm.nih.gov/compound/44566111#.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4446501&req=5

fig1: 2D chemical structure of full-length PACAP38 (CID 44566111). The chemical structure was retrieved using the publicly available PubChem database source, accessible at https://pubchem.ncbi.nlm.nih.gov/compound/44566111#.
Mentions: PACAP (molecular formula C203H331N63O53S; for details on PACAP38 chemical structure please refer to Figure 1) was originally isolated from an ovine hypothalamus extract [8]. Two PACAP isoforms have been identified, a 38-amino-acid form (PACAP38) and a C-terminally truncated 27-amino-acid form (PACAP27). It belongs to the secretine, glucagon, and peptide histidine-isoleucine (PHI) superfamily and binds to an overlapping group of receptors. PACAP receptors are G protein-coupled receptors and can be classified into two main groups, PAC1 and VPAC (including VPAC1 and VPAC2 subtypes), both of which activate adenylate cyclase with consequent stimulation of cAMP production and IP accumulation [9, 10]. In distinct cell types, PACAP is able to trigger different pathways, depending on which receptor splice variants are expressed, peptide concentration being used, and other biological factors. Among PACAP functions, the one that mostly emerges is its strong cytoprotective role, promoting survival in many types of neuronal and nonneuronal cells and tissues, including lymphocytes, chondrocytes, endothelial cells, Schwann cells, liver, lung, and ovary [11–17]. In vitro and in vivo studies have shown that the peptide acts through the PAC1 receptors to stimulate various downstream executors of the protein kinase A and C (PKA and PKC) pathways [18–21]. It also activates ion channels, β-arrestin signalling, and mitogen-activated protein (MAP) kinase in some tissues [22, 23]. PACAP and its receptors have been detected in multiple organs, with the highest levels in endocrine glands and in the central nervous system. Lower expression has been identified in gastrointestinal, respiratory, cardiovascular, and urogenital systems [24, 25]. Ultrastructural studies have also revealed that PACAP immunoreactivity is mainly localized near the plasma membrane, in the rough endoplasmic reticulum, in the Golgi's apparatus, and in the cytoplasmic matrix [26–28]. Such a broad distribution of PACAP in several tissues/organs, together with the variety of signalling pathways shown to be activated, poses the peptide in a position suitable to be considered a key drug candidate with the potential to ameliorate a wide spectrum of disorders, including diabetes and its major complications.

Bottom Line: Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available.In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state.Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.

View Article: PubMed Central - PubMed

Affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.

ABSTRACT
Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available. In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state. Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.

No MeSH data available.


Related in: MedlinePlus