Peptide Hormones

Peptide Hormones

Peptide Hormones

The word “hormone” was first introduced by William Mortlock Bayliss and Ernest Henry Starling in 1904. They coined the term using the Greek word ὁρμῶν, which means “to excite.” Two years earlier, the two physiologists published a paper demonstrating that instilling acid into the duodenum caused pancreatic secretion despite denervation of both organs [1]. This elegant experiment suggested the existence of a chemical messenger (initially named “secretin”) acting independently of the nervous system.

According to Bayliss and Starling, luminal agents stimulate the release of secretin, which travels to the pancreas through the bloodstream. In other words, they challenged the widely accepted "nervism" theory established by Pavlov and his adepts by suggesting a parallel non-nervous mechanism by which an organ can remotely influence other organs. Additionally, it laid the groundwork for the development of endocrinology as a discipline and the study of hormones [2].

This article aims to briefly describe the main characteristics of hormones, with a particular focus on peptide hormones. We will examine their structure, mechanisms of production and secretion, and their mechanisms of action. As a final example, we will look into one of medicine's most important discoveries: insulin, exemplifying the concepts discussed throughout the article.

What are Hormones?

Bayliss and Starling defined a hormone as a substance produced in one part of the body and carried by the blood or lymph to some other part, the activity of which is thereby modified [3]. Its definition is similar to the current one: a signaling molecule sent to distant organs that controls physiology and behavior in multicellular organisms [4].

Types of Hormones

There are numerous molecules within an organism that meet the previous definition and are therefore classified as hormones. Hormones can be classified into the following categories based on their chemical structure:

  • Steroid Hormones: Most of them are synthesized from cholesterol, so they share a similar structure. Steroid hormones are soluble in lipids due to their lipidic nature. There are several hormones of this type, such as cortisol and aldosterone (secreted by the adrenal cortex), estrogen and progesterone (secreted by the ovaries and placenta), and testosterone (secreted by the testes) [5].
  • Amine Hormones: A group of hormones derived from the amino acid tyrosine. Among the amine hormones are thyroxine and triiodothyronine (secreted by the thyroid), or epinephrine and norepinephrine (secreted by the adrenal medulla) [5].
  • Protein and Peptide Hormones: Protein and peptide hormones are macromolecules comprising a chain of amino acids. Protein hormones consist of chains of more than 100 amino acids, whereas peptide hormones have less than 100. To simplify the concept, in this article, we will exclusively refer to both as peptide hormones. Glucagon and insulin are examples of peptide hormones secreted by the pancreas.

Let's refresh some of the basic concepts related to proteins before diving even deeper into peptide hormones.

What are Proteins?

Proteins are macromolecules comprising a chain of amino acids linked by peptide bonds. They are synthesized by ribosomes, the macromolecular machinery of the cell that translates the genetic sequence into proteins [6].

Ribosomes are mainly found at the rough end of the endoplasmic reticulum. To synthesize proteins, they "read" the nucleotide sequence of mRNA molecules. There is an amino acid associated with every sequence of three mRNA nucleotides (known as a codon). As the ribosome "reads" the first codon, it adds the amino acid that corresponds to that codon. Afterward, the ribosome moves to the next codon and bonds the corresponding amino acid to the first one. Ribosomes repeat this process until they reach a stop codon, which ends the sequence [6]. In this way, the ribosome builds an amino acid chain as it reads through mRNA.

Peptide Hormones: Some Examples

This section describes some peptide hormones, their synthesis, and their main actions on the body.

  • Adrenocorticotropic Hormone (ACTH): Secreted by the anterior pituitary gland, ACTH triggers the production and release of cortisol and androgens by the adrenal gland in response to biological stress [7].
  • Oxytocin: A peptide hormone produced by the hypothalamus and released by the posterior pituitary. Oxytocin regulates human behavior including social bonding, reproduction, and childbirth [8-10].
  • Prolactin: The hormone prolactin, also known as lactotropin and mammotropin, plays a crucial role in metabolism, immune system regulation, and milk production in mammals. It is secreted by the pituitary gland [11].
  • Thyroxine: It is released in response to the thyroid-stimulating hormone. Thyroxine is converted into triiodothyronine, the active form that stimulates metabolism [5].

This is only a small list of hormones. There are more than 30 known peptide hormones within the human body with various physiological and behavioral effects.

Peptide Hormone Synthesis, Storage, and Secretion

Initially, peptide hormones are synthesized as large proteins without biological activity. These first proteins are called preprohormones. The endoplasmic reticulum then cleaves them into smaller proteins or prohormones. The prohormones are then transferred to the Golgi apparatus and packed into secretory vesicles. The prohormones are cleaved again by enzymes found in the vesicles to produce the biologically active hormone [5].

Hormone-containing vesicles are stored in the cytoplasm until secretion is needed. Vesicles then fuse to the plasma membrane, releasing their contents into extracellular fluid or the bloodstream. This secretory process is known as exocytosis. As peptide hormones are water soluble, they easily enter the circulatory system to reach their target tissues [5].

Exocytosis is usually triggered by increased calcium concentration in the cytosol as a result of depolarization of the plasma membrane. In other cases, stimulation of an endocrine receptor initiates the release of the hormone by increasing cyclic adenosine monophosphate (cAMP) [5].

Hormones like epinephrine or norepinephrine are secreted within seconds after the adrenal medulla is stimulated and they act within another few seconds. Others, like thyroxine or growth hormone, take months to work fully. Consequently, each hormone has an onset and duration of action specific to its control function [5].

Hormone Signaling Mechanisms

Hormones can be classified into several categories based on their signaling mechanisms:

  • Endocrine Hormones: After being released into the bloodstream, the hormone acts on a target cell in a different location within the organism.
  • Paracrine Hormones: The hormone acts on nearby cells without entering the bloodstream. Target cells are a different cell type from secretory cells.
  • Autocrine Hormones: The hormone acts on the same cells that secreted it without entering the bloodstream.

Hormone Receptors

Hormones reach their target organs and tissues through the bloodstream or extracellular fluid. Every target cell has between 2000 and 100,000 receptors specific to the hormone that it responds to [5]. The hormone receptors are located in different places within cells:

  • Cytoplasmic Hormone Receptors: Hormones must enter cells to reach their receptors, as they are located in the cytoplasm. Steroid hormone receptors are an example of cytoplasmic hormone receptors [5].
  • Nuclear Hormone Receptors: These receptors are in the cellular nucleus. For instance, receptors for thyroid hormones are located in the cellular nucleus and are believed to be associated with one or more of the chromosomes.
  • Cell Membrane Hormone Receptors: These receptors are found within the cell membrane. In most cases, peptide hormones bind to cell membrane receptors.

When a hormone binds to its receptor, it forms a hormone-receptor complex. This event activates the receptor and initiates the hormone response. Hormones elicit a variety of receptors and responses. We will examine the receptors that peptide hormones usually bind to.

  • G Protein-Linked Hormone Receptors: These receptors are embedded in the cell membrane. Some parts of the receptors are exposed to the extracellular space while others protrude into the cytoplasm. These inner protrusions are often associated with heterotrimeric guanosine triphosphate-binding proteins. A hormone binds to the extracellular region of the receptor, causing a conformational change that results in intracellular signals, such as opening an ion channel or changing the activity of an enzyme [5].
  • Enzyme-Linked Hormone Receptors: The inner region of these receptors is bound to an enzyme that is activated (or inactivated) upon hormone binding. Other receptors have intrinsic enzymatic activity. An enzyme-linked hormone receptor is the receptor for leptin, a hormone that regulates appetite and energy balance [5].

Second Messenger Systems

Upon activating the receptor, a secondary intracellular response or messenger mechanism is activated to mediate the hormone response. Let's take a closer look at some of these mechanisms.

  • Adenylyl Cyclase-cAMP: The adenylyl cyclase-cAMP system is activated by stimulatory G proteins upon receptor activation. G proteins catalyze the conversion of cytoplasmic ATP into cAMP, which activates cAMP-dependent protein kinases. By phosphorylating specific cell proteins, these kinases trigger biochemical reactions that drive the cell's response to hormones [5].
  • Cell Membrane Phospholipid: Hormones activate receptors that are coupled to the enzyme phospholipase C. This enzyme breaks down phospholipids in the cell membrane, originating inositol triphosphate and diacylglycerol. These molecules mobilize calcium ions from mitochondria and the endoplasmic reticulum, activating downstream biochemical responses [5].

Hormones do not all activate secondary messenger systems. Other hormones, especially steroid hormones, regulate gene expression and modulate protein synthesis by interacting directly with DNA.

After learning what hormones are and how they work, we will see the concepts discussed in an exciting example. We will discuss one of the most well-studied hormones in the human body: insulin.

Insulin

Insulin is a peptide hormone composed of 51 amino acids. It is secreted by pancreatic β-cells and promotes the storage of metabolic fuels. High blood glucose levels, usually after a meal, trigger the release of insulin, which induces cells within the organism to absorb glucose [12,13].

  • Eliciting Insulin Secretion: Pancreatic β-cells possess a glucose-sensing mechanism that impels the cells to secrete the exact amount of insulin required to keep glucose levels (or glycemia) stable. The glucose metabolic rate of β-cells is the primary determinant of insulin secretion [13]. In other words, the higher the glucose metabolic rate in β-cells, the more insulin is secreted.
  • Secretion of Insulin: High levels of glucose in the bloodstream increase the metabolic rate in β-cells, which leads to higher ATP production (see our bioenergetics article to learn more). As ATP concentrations in the cytoplasm increase, ATP-sensitive potassium channels close, leading to depolarization of the plasma membrane and activation of calcium channels. Acute increases in intracellular calcium levels cause insulin secretory granules to be released by the cells through exocytosis [13].
  • Insulin Receptors and Secondary Message System: Insulin receptors include insulin-like growth factor I and insulin receptor-related receptors. In response to insulin binding to these receptors, intracellular pathways are activated, resulting in glucose transporter type 4 (GLUT4) translocation from the cytoplasm to the cell membrane. GLUT4 reduces blood glucose levels by absorbing circulating glucose into the cytoplasm (particularly in muscles and adipose tissue). Furthermore, insulin promotes glucose storage in the liver by stimulating glycogen synthesis. Additionally, it induces the synthesis of lipids and inhibits their degradation [14].

Frederick Banting and Charles Best discovered insulin 100 years ago. As a result of this revolutionary achievement, type I diabetes became a medically manageable chronic condition instead of a fatal diagnosis. Dying patients miraculously recovered after receiving the hormone treatment. The discovery of insulin and its rapid industrial production is still considered one of the most significant milestones in medical history. After selling the patent for insulin back to the University of Toronto for 1 CAD, Banting remarked that “insulin belongs to the world, not to me” [15]. It was a decision that has saved millions of lives and is a reminder of the power of altruism.

Peptide Hormones in Health Optimization Medicine and Practice (HOMe/HOPe)

Many clinicians are always using various peptide hormones in their clinical practice but this field is growing fast and is challenging to navigate. 

If you are ready to learn how to use peptide hormones in clinical practice, check out the HOMe/HOPe Peptide Hormones module, one of the Advanced Practice modules of the HOMe/HOPe clinical certification. This module dives deep into various peptide hormones, clinical indications, dosing, precautions, and the physiological underpinnings.  

Check out the Peptide Hormones module in the Advanced HOMe/HOPe Course here.

Written by Ferran Riaño-Canalias, PhD

 

References

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  2. Modlin IM, Kidd M, Farhadi J. Bayliss and Starling and the nascence of endocrinology. Regul Pept. 2000;93(1):109-123. doi:10.1016/S0167-0115(00)00182-8

  3. White A, Levine R. History of Hormones. In: Goldberger RF, Yamamoto KR, eds. Biological Regulation and Development: Hormone Action. Springer US; 1982:1-24. doi:10.1007/978-1-4684-1125-6_1

  4. Shuster M. Biology for a Changing World, with Physiology. Second edition. W.H. Freeman; 2014.

  5. Guyton AC. Guyton and Hall Textbook of Medical Physiology. 14th edition. Elsevier; 2021.

  6. Albert L. Lehninger. Lehninger Principles of Biochemistry. W.H. Freeman; 2005. Accessed September 21, 2023. http://archive.org/details/lehningerprincip00lehn_0

  7. Morton IK, Hall JM. Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media; 2012.

  8. Audunsdottir K, Quintana DS. Oxytocin’s dynamic role across the lifespan. Aging Brain. 2022;2:100028. doi:10.1016/j.nbas.2021.100028

  9. Leng G, Leng RI. Oxytocin: A citation network analysis of 10,000 papers. J Neuroendocrinol. 2021;33(11):e13014. doi:10.1111/jne.13014

  10. Francis DD, Young LJ, Meaney MJ, Insel TR. Naturally Occurring Differences in Maternal Care are Associated with the Expression of Oxytocin and Vasopressin (V1a) Receptors: Gender Differences. J Neuroendocrinol. 2002;14(5):349-353. doi:10.1046/j.0007-1331.2002.00776.x

  11. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice. Endocr Rev. 1998;19(3):225-268. doi:10.1210/edrv.19.3.0334

  12. Derewenda U, Derewenda Z, Dodson GG, Hubbard RE, Korber F. Molecular Structure of insulin: The insulin monomer and its assembly. Br Med Bull. 1989;45(1):4-18. doi:10.1093/oxfordjournals.bmb.a072320

  13. Campbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol. 2021;22(2):142-158. doi:10.1038/s41580-020-00317-7

  14. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806. doi:10.1038/414799a

  15. Sims EK, Carr ALJ, Oram RA, DiMeglio LA, Evans-Molina C. 100 years of insulin: celebrating the past, present and future of diabetes therapy. Nat Med. 2021;27(7):1154-1164. doi:10.1038/s41591-021-01418-2

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