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5-HT7 receptor signaling: improved therapeutic strategy in gut disorders.

Kim JJ, Khan WI - Front Behav Neurosci (2014)

Bottom Line: However, the majority of the body's 5-HT is produced in the gut by enterochromaffin (EC) cells.Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections.This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, McMaster University Hamilton, ON, Canada.

ABSTRACT
Serotonin (5-hydroxytryptamine; 5-HT) is most commonly known for its role as a neurotransmitter in the central nervous system (CNS). However, the majority of the body's 5-HT is produced in the gut by enterochromaffin (EC) cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental colitis. 5-HT7 receptors are expressed in the gut and very recently, we have shown evidence of 5-HT7 receptor expression on intestinal immune cells and demonstrated a key role for 5-HT7 receptors in generation of experimental colitis. This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

No MeSH data available.


Related in: MedlinePlus

Distribution of 5-HT7 receptors in the gut and proposed roles in gut function. 5-hydroxytryptamine (5-HT) released from enterochromaffin cells can act on surrounding 5-HT7 receptors that are expressed by smooth muscle cells, enteric neurons, enterocytes, and immune cells. Activation of 5-HT7 receptors can influence muscle tone, enteric neuron excitation, and have been proposed to inhibit SERT activity and promote inflammation by activation of LP dendritic cells (DCs).
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Figure 1: Distribution of 5-HT7 receptors in the gut and proposed roles in gut function. 5-hydroxytryptamine (5-HT) released from enterochromaffin cells can act on surrounding 5-HT7 receptors that are expressed by smooth muscle cells, enteric neurons, enterocytes, and immune cells. Activation of 5-HT7 receptors can influence muscle tone, enteric neuron excitation, and have been proposed to inhibit SERT activity and promote inflammation by activation of LP dendritic cells (DCs).

Mentions: Specifically within the gut, 5-HT7 receptors are expressed on smooth muscle cells, enteric neurons, and within the solitary intestinal lymphoid tissue, small-sized intestinal lymphoid structures scattered through the small intestine (Tonini et al., 2005; Guseva et al., 2014). Recently, we have shown that the 5-HT7 receptor is also expressed on intestinal LP DCs (Kim et al., 2013a; Figure 1). DCs represent a heterogeneous population with functional diversity with different DC subsets having distinct sets of cell surface antigens. Although CD11c is the classical integrin marker used to distinguish DCs from macrophages (whereby CD11b+ CD11c− and CD11b+/− CD11chigh are classified as macrophages and DCs, respectively), this becomes more difficult when distinguishing between LP macrophage and DC populations, as LP macrophages express both CD11b and CD11c markers (Mowat and Bain, 2011). Therefore, it is important to use differential expression of integrin CD103 (αE integrin) to reliably distinguish between these two populations. We found that isolated intestinal CD103+ CD11c+ cells were positive for 5-HT7 receptor expression whereas no significant amount was detected on CD103− CD11c+ cells. Adding to this finding, Guseva et al. (2014) recently reported that CD11c+ CD86+ cells colocalize with 5-HT7 receptor staining in colon samples collected from both inflamed and non-inflamed areas of patients with CD. CD86 is a co-stimulatory molecule found on mature DCs. These findings suggest that 5-HT7 receptor expressed by DCs may play a role in modulating intestinal inflammation in this patient population.


5-HT7 receptor signaling: improved therapeutic strategy in gut disorders.

Kim JJ, Khan WI - Front Behav Neurosci (2014)

Distribution of 5-HT7 receptors in the gut and proposed roles in gut function. 5-hydroxytryptamine (5-HT) released from enterochromaffin cells can act on surrounding 5-HT7 receptors that are expressed by smooth muscle cells, enteric neurons, enterocytes, and immune cells. Activation of 5-HT7 receptors can influence muscle tone, enteric neuron excitation, and have been proposed to inhibit SERT activity and promote inflammation by activation of LP dendritic cells (DCs).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263172&req=5

Figure 1: Distribution of 5-HT7 receptors in the gut and proposed roles in gut function. 5-hydroxytryptamine (5-HT) released from enterochromaffin cells can act on surrounding 5-HT7 receptors that are expressed by smooth muscle cells, enteric neurons, enterocytes, and immune cells. Activation of 5-HT7 receptors can influence muscle tone, enteric neuron excitation, and have been proposed to inhibit SERT activity and promote inflammation by activation of LP dendritic cells (DCs).
Mentions: Specifically within the gut, 5-HT7 receptors are expressed on smooth muscle cells, enteric neurons, and within the solitary intestinal lymphoid tissue, small-sized intestinal lymphoid structures scattered through the small intestine (Tonini et al., 2005; Guseva et al., 2014). Recently, we have shown that the 5-HT7 receptor is also expressed on intestinal LP DCs (Kim et al., 2013a; Figure 1). DCs represent a heterogeneous population with functional diversity with different DC subsets having distinct sets of cell surface antigens. Although CD11c is the classical integrin marker used to distinguish DCs from macrophages (whereby CD11b+ CD11c− and CD11b+/− CD11chigh are classified as macrophages and DCs, respectively), this becomes more difficult when distinguishing between LP macrophage and DC populations, as LP macrophages express both CD11b and CD11c markers (Mowat and Bain, 2011). Therefore, it is important to use differential expression of integrin CD103 (αE integrin) to reliably distinguish between these two populations. We found that isolated intestinal CD103+ CD11c+ cells were positive for 5-HT7 receptor expression whereas no significant amount was detected on CD103− CD11c+ cells. Adding to this finding, Guseva et al. (2014) recently reported that CD11c+ CD86+ cells colocalize with 5-HT7 receptor staining in colon samples collected from both inflamed and non-inflamed areas of patients with CD. CD86 is a co-stimulatory molecule found on mature DCs. These findings suggest that 5-HT7 receptor expressed by DCs may play a role in modulating intestinal inflammation in this patient population.

Bottom Line: However, the majority of the body's 5-HT is produced in the gut by enterochromaffin (EC) cells.Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections.This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, McMaster University Hamilton, ON, Canada.

ABSTRACT
Serotonin (5-hydroxytryptamine; 5-HT) is most commonly known for its role as a neurotransmitter in the central nervous system (CNS). However, the majority of the body's 5-HT is produced in the gut by enterochromaffin (EC) cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental colitis. 5-HT7 receptors are expressed in the gut and very recently, we have shown evidence of 5-HT7 receptor expression on intestinal immune cells and demonstrated a key role for 5-HT7 receptors in generation of experimental colitis. This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

No MeSH data available.


Related in: MedlinePlus