Mechanism of Hormone Action by Extracellular and Intracellular receptors

Hormones are biochemical messengers produced by glands in the endocrine system and secreted into the bloodstream to regulate various physiological processes in the body. They play a crucial role in maintaining homeostasis and influencing a wide range of functions, including:

• Metabolism: Hormones such as insulin and glucagon regulate blood sugar levels and energy utilization.
• Growth and Development: Growth hormone (GH) stimulates growth and cell reproduction.
• Reproduction: Sex hormones like estrogen and testosterone control reproductive functions and secondary sexual characteristics.
• Mood and Stress Response: Hormones such as cortisol and adrenaline are involved in the body’s response to stress and can affect mood and behavior.
• Regulation of Water and Electrolytes: Hormones like aldosterone and antidiuretic hormone (ADH) help manage fluid balance and blood pressure.

Hormones exert their effects by binding to specific receptors on target cells, initiating a cascade of biochemical events that lead to a specific cellular response. Their action can be rapid or gradual, depending on the hormone and its target tissue. Overall, hormones are vital for coordinating complex bodily functions and maintaining health.

Mechanism of Hormone action

The molecular mechanism of hormone action is divided into two modes;

1. Mechanism of Hormone action by the extracellular receptors
2. Mechanism of Hormone action by the intracellular receptors.

Mechanism of Hormone action by the Extracellular Receptors

The action of hormones through extracellular receptors, particularly via fixed membrane receptors, plays a crucial role in cellular signaling and regulation. These processes are pivotal for maintaining homeostasis and coordinating physiological responses in the body. Unlike lipid-soluble hormones that can penetrate cell membranes, amino acid-derived and peptide hormones rely on membrane-bound receptors to exert their effects. Below is an elaboration of this mechanism, emphasizing its complexity and functionality.

• Hormone-Receptor Interaction:
  • Amino acid derivatives and polypeptide hormones bind specifically to receptor proteins located on the plasma membrane of target cells.
  • This binding is specific; for instance, insulin receptors consist of four protein subunits (two α and two β subunits). The α-subunits are external and interact with insulin, while the β-subunits extend into the cytoplasm.
• Initiation of Signaling Pathways:
  • Upon hormone binding, conformational changes occur in the receptor, activating intrinsic enzymatic functions. For insulin, this activation involves the β-subunits acting as tyrosine kinases, which catalyze the phosphorylation of tyrosine residues in the receptor and associated substrates.
  • The hormone binding leads to the generation of a signaling cascade within the cell, as the hormone is referred to as the first messenger, while the resultant intracellular mediators, such as cyclic adenosine monophosphate (cAMP), are termed second messengers.
• Role of G-Proteins:
  • Many signaling pathways involve G-proteins, which are peripheral membrane proteins composed of three subunits: α, β, and γ. In their inactive state, G-proteins are bound to GDP.
  • When a hormone binds to its receptor, the G-protein is activated, exchanging GDP for GTP. The activated α-subunit dissociates and stimulates enzymes such as adenylyl cyclase, leading to increased levels of cAMP from ATP.
• Cyclic AMP as a Second Messenger:
  • cAMP functions as a crucial mediator within the cell. It activates protein kinases, which phosphorylate specific target proteins, inducing changes in their activity.
  • This phosphorylation process significantly amplifies the signal, as one activated protein kinase can, in turn, activate numerous substrates, thereby facilitating a large-scale response from minimal hormone quantities.
• Further Second Messenger Systems:
  • Besides cAMP, other second messengers such as cyclic guanosine monophosphate (cGMP), diacylglycerol (DG), and inositol triphosphate (IP3) also play roles in cellular signaling.
  • For example, DG remains within the plasma membrane and activates protein kinase C, while IP3, being water-soluble, triggers the release of calcium ions from the endoplasmic reticulum, further propagating the signaling cascade.
• Signal Amplification:
  • The process of signal amplification is a hallmark of hormone action through membrane receptors. One hormone molecule can activate multiple G-proteins, leading to the activation of numerous adenylyl cyclase enzymes, which produce vast amounts of cAMP.
  • This cascade effect ensures that even small hormone concentrations can generate significant physiological responses, such as the rapid release of glucose in response to adrenaline.
• Regulation of Signaling:
  • The action of second messengers is tightly regulated. For instance, phosphodiesterase (PDE) continuously breaks down cAMP, terminating the signal and preventing excessive cellular responses.
  • This feedback mechanism ensures that cellular activities remain balanced, highlighting the importance of regulation in hormonal signaling.
• Antagonistic and Synergistic Effects:
  • Hormones can exert opposing effects, known as antagonistic effects. For example, insulin lowers blood glucose levels, while glucagon raises them, demonstrating a balance in metabolic regulation.
  • Conversely, synergistic effects occur when multiple hormones work together to produce a more substantial outcome. This is evident in lactation, where several hormones, including estrogens and prolactin, cooperate for milk production and ejection.

Mechanism of Hormone action by the intracellular receptors

The mode of hormone action through intracellular receptors is fundamental to understanding how lipid-soluble hormones exert their effects at the cellular level. These hormones, primarily steroid hormones, are capable of diffusing across cell membranes and directly influencing gene expression within target cells. The process is characterized by a series of precise and sequential interactions that facilitate the regulation of various physiological functions.

• Hormone Structure and Transport:
  • Lipid-soluble hormones, such as steroid hormones, are synthesized from cholesterol and are not soluble in water. Once released from the endocrine cells, they bind to transport proteins in the bloodstream, which keep them soluble and facilitate their transport to target tissues.
• Diffusion Across Membranes:
  • Upon reaching the target cell, these hormones detach from their carrier proteins and diffuse through the lipid bilayer of the plasma membrane. Their hydrophobic nature allows them to traverse the membrane with ease, distinguishing them from water-soluble hormones that require surface receptors.
• Binding to Intracellular Receptors:
  • Inside the cell, steroid hormones typically bind to specific receptor proteins located in the cytoplasm or the nucleus. This binding forms a hormone-receptor complex. For example, glucocorticoids, a class of steroid hormones, interact with glucocorticoid receptors, while thyroid hormones bind to thyroid hormone receptors.
• Hormone-Receptor Complex Activation:
  • Once formed, the hormone-receptor complex undergoes a conformational change, allowing it to enter the nucleus if it is not already located there. This complex then associates with specific regulatory sites on the DNA, known as hormone response elements (HREs).
• Gene Regulation:
  • The binding of the hormone-receptor complex to HREs facilitates the transcription of specific genes. This process involves the activation or repression of gene expression, resulting in the synthesis of mRNA. The mRNA is then translated into proteins, including enzymes that catalyze critical biochemical reactions within the cell.
• Role of Heat Shock Proteins:
  • In the context of cellular stress, heat shock proteins (HSPs) play an essential role. They assist in the proper folding of proteins, particularly during conditions such as heat shock. When lipid-soluble hormones bind to their receptors, they may also modulate the expression of HSP genes, enhancing the cell’s ability to manage stress by preventing protein misfolding.
• Comparison with Water-Soluble Hormones:
  • The actions of lipid-soluble hormones tend to be slower and more prolonged than those of water-soluble hormones, which typically induce rapid responses through membrane-bound receptors. This slower action is attributed to the need for gene transcription and subsequent protein synthesis.
• Physiological Effects:
  • Through these mechanisms, lipid-soluble hormones regulate a wide range of physiological processes, such as metabolism, immune response, and developmental changes. For instance, steroid hormones are involved in metabolic regulation, while thyroid hormones are critical for growth and development.
• Examples of Intracellular Hormones:
  • Besides steroid hormones, other lipid-soluble hormones, such as vitamin D and thyroxine, also utilize intracellular receptors. They similarly diffuse through cell membranes, bind to their respective receptors, and initiate gene transcription within the nucleus.

Role of Hormones as Messengers and Regulators

Hormones play a crucial role as messengers and regulators within biological systems, facilitating communication between various organs and systems. By understanding the functions and mechanisms of hormones, one can appreciate their significance in maintaining homeostasis. This overview delineates the key roles of hormones, focusing on their messenger capabilities through the hypothalamo-hypophysial axis and their regulatory functions via feedback control mechanisms.

1. Hormones as Messengers
   • The hypothalamus, a critical region of the forebrain, contains neurosecretory cells located in its hypothalamic nuclei. These neurons release hormones known as neurohormones, which are instrumental in regulating various physiological processes.
   • Neurohormones act as chemical messengers that enter the bloodstream and travel to the anterior lobe of the pituitary gland. This transport occurs through the hypophysial portal veins.
   • Upon reaching the pituitary gland, neurohormones stimulate the release of additional hormones, which play pivotal roles in various bodily functions. This interaction is fundamental to the functioning of the endocrine system, hence the term releasing hormones or releasing factors.
2. Hormones as Regulators
   • Homeostasis refers to the maintenance of stable internal conditions within the body. Hormones are essential in regulating cellular functions and ensuring that various bodily systems operate optimally.
   • The secretion of hormones can be controlled by multiple factors, including other hormones. This regulation often employs feedback control mechanisms, which can be classified into two main types:
   (i) Positive Feedback Control
   • In positive feedback, when the level of a specific hormone—such as thyroxine—falls below normal levels, it triggers a response to increase its production. For example, low thyroxine levels stimulate the hypothalamus to secrete more thyrotropin-releasing hormone (TRH).
   • This increase in TRH leads to a heightened secretion of thyroxine from the thyroid gland, creating a reinforcing cycle aimed at restoring hormone levels to their normal range.
   (ii) Negative Feedback Control
   • Negative feedback operates inversely to positive feedback, serving as a regulatory mechanism to maintain equilibrium. For instance, TRH from the hypothalamus prompts the pituitary gland to release thyroid-stimulating hormone (TSH).
   • TSH stimulates the thyroid gland to produce thyroxine. When thyroxine levels rise to a sufficient concentration, they exert an inhibitory effect on the hypothalamus. This inhibition results in decreased production of both TRH and TSH, ultimately lowering thyroxine secretion. This feedback loop is crucial for maintaining hormonal balance and preventing excessive hormone levels in the bloodstream.