# Paracrine regulator

Cell signaling can be divided into three major categories: autocrine regulation, endocrine regulation, and paracrine regulation. Autocrine signaling occurs when regulator molecules are secreted by a cell and received by receptor molecules on the same cell. In endocrine signaling, regulator molecules are released by endocrine glands into the bloodstream to produce activity in distant cells. Lastly, in paracrine signaling, the paracrine regulators are released by a cell to produce an activity on a neighboring cell within the same tissue.
Paracrine regulation is vital to many cellular processes. Examples of paracrine signaling include the regulation of insulin secretion, the regulation of blood flow, and the regulation of epidermal homeostasis.

## Insulin Secretion

Insulin is secreted by beta cells within the pancreatic islets of Langerhans and regulates the movement of glucose from the bloodstream into the cells for metabolism. When the blood glucose levels are high, for example right after a meal, the beta cells of the pancreas are stimulated to release insulin. Insulin is a hormone that stimulates cells throughout the body to take up glucose to metabolize, therefore decreasing blood glucose levels. This occurs when ATP levels rise due to the increase in glucose metabolism, closing ATP-sensitive potassium channels on the beta cells. The subsequent depolarization of the cell opens voltage-gated calcium channels leading to an influx of Ca$^{2+}$ in the cell, which is required for the release of insulin.
The secretion of insulin by these beta cells is regulated by the paracrine activity of alpha and delta cells also located within the pancreatic islets, and the autocrine activity of neighboring beta cells. Alpha cells in the pancreatic islet release glucagon, a hormone that regulates blood glucose levels antagonistically to insulin by stimulating the breakdown of glycogen stores to increase glucose concentrations in the bloodstream. However, glucagon can also activate receptors on pancreatic beta cells to increase insulin secretion. This will only occur in slightly hyperglycemic conditions because these conditions stimulate a depolarization of the cell by closing potassium channels and opening calcium channels that is necessary for the release of insulin to occur, as previously discussed. Alpha cells exhibit a few other paracrine functions that stimulate the secretion of insulin by pancreatic beta cells. These include the release of GLP-1 and corticotropin-releasing hormone (CRH).
Pancreatic delta cells also function in paracrine regulation of insulin and glucagon secretion by releasing somatostatin, or growth hormone-inhibiting hormone (GHIH). Somatostatin acts as an inhibitor to both the release of glucagon by alpha cells and the release of insulin by beta cells.

## Blood Flow

Another cellular process that is regulated by paracrine signaling is blood flow. Vasoconstriction and vasodilation are the respective constriction and dilation of blood vessels throughout the body to precisely control the flow of blood. This occurs myogenically by smooth muscle cells surrounding the vessels, metabolically by the changes in oxygen and carbon dioxide concentrations, and through local paracrine signaling.
The paracrine signaling mechanism of controlling blood flow relies on the release of hormones from the bloodstream and the immune system. Platelets in the bloodstream release the hormones thromboxane A$_2$, thrombin, and serotonin. When there is an absence of intact endothelium of the blood vessels, these hormones will diffuse to the vascular smooth muscle tissue where they stimulate contraction, and therefore vasoconstriction, leading to a decrease in blood flow to that area. When the endothelium is intact, the serotonin and thrombin released by the platelets as well as ADP stimulate the endothelial cells to produce nitric oxide and prostacyclin. These signal molecules then stimulate the relaxation of the vascular smooth muscle, causing vasodilation and an increase in blood flow.
Mast cells, a type of white blood cell, also contribute to the paracrine regulation of blood flow by releasing histamine. During an immune response, histamines are released by the mast cells and stimulate the endothelial cells to produce nitric oxide and prostacyclin. Again, this signals the relaxation of the vascular smooth muscle tissue, causing vasodilation and an increase in blood flow.

## Epidermal Homeostasis

Epidermal homeostasis is maintained by the replacement of skin cells during tissue turnover and injury, as well as the prevention of an excess of skin cell development. This is controlled by the proliferation and differentiation of keratinocytes in the epidermis that is controlled by paracrine signaling. Without proper regulation, skin conditions such as psoriasis and a lack of wound repair may occur.
In the dermis, the tissue layer below the epidermis, fibroblast cells are located. Fibroblast cells contribute to the formation and maintenance of connective tissue in the body.$^$ These fibroblast cells release many hormones that regulate epidermal keratinocytes, two of which include keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). KGF and GM-CSF are both hormones that stimulate the regeneration of keratinocytes in the epidermis and are both regulated by the keratinocyte-derived factor IL-1. IL-1 is a growth factor that is released by keratinocytes under stress conditions, such as injury or UV radiation. When IL-1 is released, it stimulates the release of KGF and GM-CSF by the fibroblasts, thus inducing regeneration of keratinocytes.
Psoriasis is a condition that occurs when epidermal homeostasis is not properly controlled, and an excess of keratinocyte proliferation causes patches of thick skin lesions. EGFR is a receptor tyrosine kinase (RTK) involved in the psoriasis condition. EGFR and its many ligands are overproduced or hyperactive in psoriasis patients, leading to a hyper-proliferation of keratinocytes in the epidermis. Two methods have been found to work relatively effectively for the treatment of psoriasis. PD-169540 is a drug that antagonistically affects the EGFR RTK, and has been shown to decrease the symptoms of psoriasis. Additionally, cetuximab is a drug commonly used for chemotherapy that is an anti-EGFR antibody. Cetuximab has been found to reduce the symptoms of psoriasis in certain cases, as it is inhibitory to the EGFR RTK.

## Conclusion

Paracrine regulation plays a vital role in many cellular processes throughout the human body. Although not exhaustive, this includes the regulation of insulin secretion, blood flow, and epidermal homeostasis. These processes as well as many others are crucial in maintaining the function of the human body. The endocrine system as a whole, including paracrine, autocrine, and endocrine methods of regulation, is a complex system that is responsible for the overall homeostasis of the body. Disruptions in this system cause a wide range of diseases and conditions that can be detrimental.