Unit 3 Hormone Receptors and Response Systems

Hormone Receptor Function and Response Systems

1st Order Receptor & Response System

Definition: The hormone must bind to its receptor, referred to as the 1st order receptor, to initiate a biological response.

Action Mechanism: Extensive response system required, including:

• Secondary, tertiary, and/or quaternary messengers and their respective receptors. These messengers amplify the signal transduced by the hormone binding to its receptor.

• Transcriptional cofactors that assist in activating or repressing target genes essential for cellular response.

Requirements for Cellular Response

For a cellular response to occur, two critical elements are paramount:

• A hormone must be present to bind to the receptor; this interaction triggers the signaling cascade necessary for action.

• A receptor must be competent to recognize and bind to the hormone. The ligand serves as the first-order receptor, regulating not only hormone activity but also its synthesis and secretion.

Hormone Regulation

Hormone synthesis and secretion can be regulated independently via:

• Transport mechanisms: These mechanisms affect how hormones enter target cells and how they circulate in the bloodstream.

• Hormones can undergo modifications (e.g., activation or degradation) through various metabolic processes, determining their overall activity. For instance, thyroid hormones require activation by deiodination to exert their effects effectively.

Hormonal Effects Depend On

Hormonal effects may not always manifest immediately and depend on:

• Availability and activity of receptors, which can be upregulated or downregulated depending on physiological conditions and prior exposure to hormones.

• The metabolic state of the cell, which may determine how efficiently hormones are utilized.

G Protein-Coupled Receptors (GPCRs)

An example of classic receptor involvement in the signaling cascade leading to cellular responses. GPCRs are significant as:

• They interact with a variety of ligands including hormones, neurotransmitters, and environmental stimulants.

• They play a pivotal role in many physiological processes and are common targets in pharmacology.

Hormone Synthesis and Secretion

Types of Hormones

1. Amines: Derivatives of amino acids, e.g., catecholamines (epinephrine, norepinephrine).

2. Proteins: Include peptide hormones such as insulin and glucagon that play critical roles in metabolism.

3. Steroids: Derived from cholesterol, e.g., cortisol, estrogens. They have varying solubility and mechanisms of transport.

4. Eicosanoids: Lipid-derived signaling molecules that mediate inflammation and immune responses.

5. Thyroid Hormones: Typically classified between proteins and steroids due to their unique synthesis and action pathways.

Synthesis and Secretion Dynamics

The synthesis dynamics vary by hormone type:

• For peptide and protein hormones, they are often synthesized in advance and stored, allowing for a quick secretion response when stimulated.

• Steroid hormones are synthesized on demand due to their lipophilic nature, which means they cannot be stored in the same way as proteins.

Hormonal Regulation

Hormonal synthesis and secretion can be directly regulated by:

• Free-standing endocrine glands: These glands can autonomously produce hormones based on internal and external stimuli.

• Hypothalamic-pituitary axis: Acts as a central regulator of endocrine functions by releasing tropic hormones.

Negative Feedback

Hormone levels can signal back to their gland of origin to decrease their own synthesis/secretion through a negative feedback loop. This is critical in maintaining homeostasis.

Tropic Hormones

These hormones regulate other endocrine glands through feedback mechanisms, playing a vital role in the overall endocrine function.

Hormone Transport Mechanisms

Transport Steps

Essential for hormone responsiveness and distribution:

• Peptide/Protein Hormones: Soluble and circulate freely in aqueous serum, allowing for immediate responsiveness.

• Steroids and Thyroid Hormones: Lipophilic hormones that may enter target cells directly, or may require plasma proteins for transports, such as albumin.

Bound Hormones vs. Free Hormones:

• Bound hormones are inactive and not available to interact with cell receptors, while only unbound (free hormones) can elicit physiological responses.

Free Hormone Hypothesis

This hypothesis posits that unbound hormones can enter cells and achieve various equilibrium states with bound hormones. Binding proteins are essential for transporting lipophilic hormones and maintaining their reserve pools.

Hormone Uptake Mechanisms

Uptake Mechanisms

• Proteins are large and hydrophilic, necessitating specialized transport systems, such as receptor-mediated endocytosis.

• Passive diffusion is utilized for small lipophilic hormones, e.g., amines, steroids that easily penetrate cell membranes; T3 and T4 are examples that act through nuclear receptors primarily.

Hormone Metabolism

Metabolic Pathways

Hormones may be metabolized into other active forms or rendered inactive. This can involve:

• Transforming a prohormone into an active hormone (e.g., T4 converted to T3, which has a higher receptor affinity, or to inactive reverse T3).

Receptor Types

Classes of Receptors

1. Nuclear Receptors:

• These act as transcription factors that regulate gene expression; they require ligand binding to activate gene response without secondary messengers.

2. Cell Surface Receptors:

• They trigger signaling cascades upon hormone binding, leading to cellular responses that are often amplified further downstream.

Mechanisms of Action for Steroid Hormones

• Steroid hormones enter cells via a combination of diffusion or transport receptors, forming a hormone-receptor complex that alters gene transcription by binding to hormone response elements (HREs). This process can either activate or inhibit gene transcription based on the ligand's action (as a transcription factor).

Signal Amplification

GPCR Signaling

• One ligand can generate thousands of secondary messengers, significantly amplifying the hormonal signal.

Signaling Events with G Proteins

1. Ligand binds to its specific receptor.

2. GDP is released, and GTP binds to the alpha subunit of the G protein.

3. The active alpha subunit interacts with effectors, such as adenylate cyclase, initiating secondary messenger pathways (e.g., cAMP production).

Feedback and Desensitization Mechanisms

• The GTPase activity of the G protein returns the signaling effects to an inactive state after the response has been completed.

• Endocytosis & Resensitization:Active G-proteins can modify receptors to prevent overstimulation but can recycle them for future use, ensuring cellular responsiveness to subsequent signals.