Malcolm Rivera
Many neural and endocrine cells possess two pathways of secretion: a regulated pathway and a constitutive pathway. The constitutive exocytosis pathway operates continually in all cells and supplies a continuous stream of vesicles containing lipids and proteins for the plasma membrane. In contrast, the regulated pathway is found only in specialized cells. The regulated secretory pathway involves the release of peptide hormones stored in granules, while the constitutive pathway involves the externalization of surface-bound proteins via a distinct set of vesicles. This raises the question of whether the proper function of these pathways requires continuous protein synthesis. The answer to this question has implications for understanding the mechanisms that regulate the sorting and transport of molecules through these pathways.
| Characteristics | Values |
|---|---|
| Type of cells | Neural and endocrine cells |
| Secretory pathways | Regulated and constitutive |
| Regulated pathway | Found in specialized cells such as neuronal, endocrine, or exocrine types |
| Constitutive pathway | Present in all cells |
| Constitutive exocytosis pathway | Operates continually in all cells |
| Regulated pathway | Releases peptide hormones stored in granules |
| Constitutive pathway | Releases other surface-bound proteins via a distinct set of vesicles |
| Regulated pathway | Requires protein synthesis |
| Constitutive pathway | Does not require protein synthesis |
| Regulated pathway | Impaired by cycloheximide treatment |
| Constitutive pathway | Unhindered by cycloheximide treatment |
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What You'll Learn
- The impact of protein synthesis inhibitors on the regulated secretory pathway
- The role of glycosaminoglycan chains in the constitutive and regulated pathways
- The presence of regulated and constitutive pathways in different cell types
- The effects of cycloheximide treatment on the cell's ability to store and secrete
- The mechanisms for sorting and transporting molecules through the pathways
The impact of protein synthesis inhibitors on the regulated secretory pathway
The secretory pathway is a complex process that ensures proteins reach their correct destinations, maintaining cellular organization, intercellular communication, and immune responses. This pathway is of particular interest in therapeutic interventions due to its involvement in a multitude of secretory molecules and diseases.
Protein synthesis inhibitors are a class of compounds that act on the secretory pathway, specifically targeting the protein translocation process across biological membranes. These inhibitors have been extensively studied for their antimicrobial and anticancer properties, as they can selectively block protein translocation, which is essential for cellular function. For instance, cancer cells rely heavily on efficient protein translocation to support their rapid growth.
In neural and endocrine cells, the impact of protein synthesis inhibitors on the regulated secretory pathway has been observed. Studies in mouse pituitary AtT-20 cells have revealed that cycloheximide treatment, a protein synthesis inhibitor, severely impairs the cell's ability to store and secrete glycosaminoglycan chains through the regulated secretory pathway. This impairment is specific to the regulated pathway, as the constitutive secretion of glycosaminoglycan chains remains unaffected by cycloheximide, indicating differential requirements for protein synthesis between the two pathways.
The regulated secretory pathway is closely associated with the function of vesicles, which mediate the transport of cargo. Vesicular transport is facilitated by specialized organelles and molecular signals that guide proteins to their specific destinations. Inhibitors of protein synthesis can disrupt this process by hindering the formation and navigation of vesicles, leading to potential functional disruptions and diseases.
Additionally, the unfolded protein response (UPR) is a crucial mechanism in the secretory pathway that alleviates ER stress by upregulating chaperone production and slowing protein synthesis. Recent studies have focused on targeting components of the UPR network, particularly the XBP1 mRNA splicing inhibitors, as potential candidates for treating multiple myeloma.
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The role of glycosaminoglycan chains in the constitutive and regulated pathways
Glycosaminoglycans (GAGs) are linear polysaccharides found on animal cell surfaces and in extracellular matrices. Their synthesis is complex and results in a domain structure that enables them to bind to protein partners. GAGs are essential for the normal functioning of nearly all adult physiological systems and are required for embryogenesis. They play important roles in development, pathogenesis, anticoagulation, metastasis, homeostasis, and angiogenesis.
Many neural and endocrine cells possess two pathways of secretion: a regulated pathway and a constitutive pathway. Peptide hormones are stored in granules and undergo regulated release, while other surface-bound proteins are externalized constitutively via a distinct set of vesicles. The regulated pathway packages GAGs with the hormone adrenocorticotropin (ACTH). Cycloheximide treatment impairs the cell's ability to store and secrete GAG chains by the regulated secretory pathway. In contrast, the constitutive pathway remains unhindered in the absence of protein synthesis, indicating that this pathway does not require new protein synthesis.
The biosynthesis of GAGs, such as heparan sulfate (HS), involves modification by enzymes in the Golgi apparatus. The chains are linked to Ser residues and are acted on by N-deacetylase/N-sulfotransferases, which replace acetyl groups with sulfate groups. The modifications define the domain structure of the GAG chains. Mature chains may be further modified at specific positions, resulting in a regulated domain structure with some heterogeneity.
Studies have examined the transport of GAG chains in the two secretory pathways, focusing on the effects of protein synthesis inhibitors. The regulated pathway is sensitive to protein synthesis arrest, while the constitutive pathway is not. This suggests that the two pathways have distinct mechanisms for sorting and transporting molecules. Further research aims to understand how protein synthesis influences the trafficking of GAG chains to the regulated pathway.
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The presence of regulated and constitutive pathways in different cell types
The regulated secretory pathway is typically found in specialized cells such as neuronal, endocrine, or exocrine cell types. However, evidence suggests that this pathway may be more widespread among different cell types than previously thought. For example, the identification of post-Golgi storage vesicles in several constitutive secretory cells indicates that these cells can also undergo exocytosis in response to stimuli.
In contrast, the constitutive secretory pathway is believed to be present in all cells. This pathway does not appear to require continuous protein synthesis for its operation. For instance, studies have shown that cycloheximide treatment, which inhibits protein synthesis, does not affect the constitutive secretion of glycosaminoglycan chains.
The differential requirements for protein synthesis between the two pathways suggest distinct mechanisms for sorting and transporting molecules. The regulated pathway is sensitive to protein synthesis inhibition, indicating that proper function may require continuous protein synthesis. This highlights the intricate regulation of cellular processes to maintain homeostasis and respond to changing environmental conditions.
Understanding the presence and regulation of these pathways in different cell types is crucial for comprehending cellular communication, signalling, and overall physiological function. Further research in this area continues to enhance our knowledge of the complex cellular processes that underlie various biological systems.
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The effects of cycloheximide treatment on the cell's ability to store and secrete
Many neural and endocrine cells have two pathways of secretion: a regulated pathway and a constitutive pathway. The regulated pathway involves the storage and release of peptide hormones from granules, while the constitutive pathway involves the externalization of surface-bound proteins via distinct vesicles.
Cycloheximide is a naturally occurring fungicide produced by the bacterium Streptomyces griseus. It is a protein synthesis inhibitor that interferes with the movement of tRNA molecules and mRNA in relation to the ribosome, blocking translational elongation. This interference with protein synthesis has been shown to severely impair the cell's ability to store and secrete certain molecules by the regulated secretory pathway.
In specific studies, cycloheximide treatment has been found to impair the cell's ability to store and secrete glycosaminoglycan chains by the regulated secretory pathway. These chains are usually packaged along with the hormone adrenocorticotropin (ACTH) and secreted through the regulated pathway. However, cycloheximide treatment disrupts this process, highlighting the requirement for protein synthesis in the regulated pathway.
On the other hand, the constitutive secretory pathway remains unaffected by cycloheximide treatment. This suggests that the constitutive pathway does not rely on continuous protein synthesis for its operation. The differential effects of cycloheximide on the two pathways indicate distinct mechanisms for sorting and transporting molecules through the constitutive and regulated pathways.
Additionally, cycloheximide has been found to induce cell death in certain cell types, such as T cells, and is often used in combination with Tumor Necrosis Factor to induce synergistic cytotoxicity. It is important to note that cycloheximide has significant toxic side effects, including DNA damage and reproductive issues, limiting its use to in vitro research applications.
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The mechanisms for sorting and transporting molecules through the pathways
Many neural and endocrine cells possess two pathways of secretion: a regulated pathway and a constitutive pathway. The constitutive exocytosis pathway operates continually in all cells, providing a continuous stream of vesicles containing lipids and proteins for the plasma membrane. Other proteins and glycoproteins are secreted via the constitutive secretory pathway and form part of the extracellular matrix.
Peptide hormones are stored in granules that undergo regulated release, while other surface-bound proteins are externalized constitutively via a distinct set of vesicles. The regulated secretory pathway is found in specialized cells such as neuronal, endocrine, or exocrine types.
The mechanisms for sorting and transporting molecules through these pathways are complex. For instance, proteins destined for the regulated secretory pathway form aggregates in the trans-Golgi network, while those destined for the constitutive secretory pathway do not. Protein aggregates containing proteins destined for regulated secretion are seen in vesicles in the process of budding from the trans-Golgi network. The aggregation occurs in response to the acidic conditions of the trans-Golgi network.
In addition, studies have shown that glycosaminoglycan chains enter the regulated secretory pathways and are packaged along with the hormone adrenocorticotropin (ACTH). Cycloheximide treatment severely impairs the cell's ability to store and secrete glycosaminoglycan chains by the regulated secretory pathway. In contrast, constitutive secretion of glycosaminoglycan chains remains unaffected by cycloheximide, indicating that this pathway does not require continuous protein synthesis.
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Frequently asked questions
The regulatory pathway is found only in specialized cells such as neuronal, endocrine, or exocrine types, while the constitutive pathway is present in all cells. The regulatory pathway involves the release of peptide hormones stored in granules, while the constitutive pathway involves the externalization of surface-bound proteins via a distinct set of vesicles.
The regulatory pathway is severely impaired by cycloheximide treatment, which inhibits the cell's ability to store and secrete glycosaminoglycan chains. In contrast, the constitutive pathway remains unhindered in the absence of protein synthesis, suggesting that it does not require new protein synthesis for operation.
The sorting and transporting of molecules through these pathways differ. Proteins destined for the regulatory pathway form aggregates in response to the acidic conditions of the trans Golgi network, while those for the constitutive pathway do not. The regulatory pathway releases vesicles in response to specific stimuli, while the constitutive pathway operates continually, supplying a stream of vesicles containing lipids and proteins for the plasma membrane.
