Cell Communication and Disease

HUBS2206 Human Biochemistry and Cell Biology Lecture 25: Disease - A Failure of Cell Communication

Learning Targets

• Cell communication mechanisms:
  • Gap junctions
  • Autocrine
  • Paracrine
  • Endocrine
• The endocrine system.
• How water-soluble hormones function, including:
  • Synthesis
  • Release
  • Transport
  • Receptors
  • Mode of action
• Lipid-soluble hormones will be covered in a future lecture.
• Key concept: Cell communication is essential for normal homeostasis.

Basics of Cell Communication

• Cells must communicate to:
  • Maintain body homeostasis.
  • Bring about coordinated changes in body physiology.
• Mechanisms are needed for cells to integrate information from the outside world.
• Cell-cell communication is a major landmark required for developing complex multicellular organisms.
• Communication is induced by extracellular signal molecules that can act locally or at a long distance.
• Cells grow, divide, or die according to the signals they receive.
• The process involves an extracellular signal molecule binding to a receptor protein, activating intracellular signaling pathways, and altering the activity of effector proteins, thereby influencing cell behavior.
• Effector proteins can alter metabolism, gene expression, or cell shape and movement.

Normal Cell Communication Pathways

• Examples of pathways include those involving genes such as WNT, TGF-B, and proteins such as MAPK, RAS, and P13K, among others.
• These pathways regulate processes like cell division and autodestruction.

Abnormal Cell-Cell Communication and Disease

• Abnormal cell-cell communication is a hallmark of:
  • Cancer
  • Infection
  • Mental and neurological disorders
  • Metabolic disorders (e.g., diabetes)
  • Congenital malformations

Altered Communication in Cancer

• Genetic changes in cancer:
  • Altered proteins along different pathways cause signals to be intercepted, amplified, or misdirected.
  • These changes hijack normal communication, leading to uncontrolled tumor growth.
• Examples include retinoblastoma, sarcomas, leukemia, some neuronal tumors, and colon cancer.

Mechanisms of Cell Communication

1. Direct Contact:
   • Juxtacrine
   • Gap junction
2. Short-Range:
   • Autocrine
   • Paracrine
   • Synaptic signaling
3. Long-Range:
   • Endocrine
   • Neuroendocrine

Local Communication by Direct Contact

• Contact-dependent communication requires physical contact between two adjacent cells.
• Effects are limited to adjacent interconnected cells of the same type.
• Allows rapid and direct communication.

JUXTACRINE

• Example: embryonic development.
• Involves integrin receptors binding to ECM proteins.

GAP JUNCTIONS

• Allows direct flow of ions and small solutes to neighboring cells.

Gap Junctions: Details

• Small intercellular channels allow ions and small molecules to pass directly from one cell to another without entering the extracellular space.
  • Most proteins and genetic material are too large to pass.
• Composed of transmembrane proteins called connexins.
• Six connexin proteins assemble to form a hemi-channel (connexon).
• Connexons from adjacent cells align to form a continuous channel between the two cells.

Gap Junctions: Occurrence and Function

• Present in most animal tissues, including connective tissue, epithelia, heart muscle, and smooth muscle of the intestine.
• Occur as small or large patches of multiple gap junctions.
• Provide electrical coupling (e.g., heart cells).
• Provide metabolic coupling, coordinating activities of individual cells within tissues and smoothing out random fluctuations in small molecule concentrations.
• Much faster spread of action potential than in chemical synapses.

Short-Range Communication

• Communication via extracellular fluid.
• Short-range soluble signals diffuse over short distances.
• Effects primarily limited to the local area.
• Target cells must have appropriate receptors to respond to extracellular signals.

PARACRINE

• Local extracellular signal (e.g., growth factors, inflammation).

AUTOCRINE

• Examples: immune system, cancer.

Synaptic (Neuronal) Communication

• Local communication allows signal transmission from one neuron to the next across synaptic clefts.
• Neurons transmit signals electrically along their axons.
• Stimulates the release of neurotransmitters, which act on target cells.
• Very fast and brief transmission.
• Neurotransmitters are chemical messengers released by nerve cells that diffuse across the synaptic cleft to activate receptors on target cells.

Long-Range Communication

• Long-distance communication through the circulatory system.

ENDOCRINE

• Hormones are chemical messengers secreted in the blood by specialized endocrine cells, transported throughout the body, and act on target cells primarily in other tissues to elicit a response.

NEUROENDOCRINE

• Involves neurohormones (e.g., antidiuretic hormone).

The Endocrine System

• Many hormones produced, including those from the hypothalamus, pituitary gland, thyroid gland, thymus, adrenal glands, pineal gland, parathyroid glands, heart, kidney, adipose tissue, digestive tract, pancreatic islets, and gonads.

Hormone Functions

• Help maintain homeostasis and respond to environmental changes.
• Help regulate:
  • Fluid and electrolyte balance
  • Metabolism (e.g., blood glucose level)
  • Contraction of cardiac and smooth muscle
  • Glandular secretion
  • Some immune functions
  • Growth and development
  • Reproduction
  • Stress response

Endocrine Disorders

• Most common causes are hypo- and hypersecretion of specific hormones (e.g., growth hormone).
• Too much hormone secreted by the endocrine gland (hypersecretion).
• Too little hormone secreted by the endocrine gland (hyposecretion).
• Reduced plasma protein binding of the hormone (too much free, biologically active hormone).
• Increased or decreased removal of the hormone from the blood.
• Abnormal tissue responsiveness of the hormone due to lack of target cell receptors or an essential enzyme.

Classification of Hormones by Chemical Structure

• Amino acid derivatives (e.g., thyroid hormones).
• Peptide hormones (polypeptides and small proteins, e.g., insulin, growth hormones; glycoproteins, e.g., TSH, EPO).
• Lipid derivatives (steroid hormones from cholesterol, e.g., sex hormones; eicosanoids from arachidonic acid).

Hormone Classification Based on Solubility

• Solubility influences mechanisms of release and mode of action.
• Water-soluble hormones (peptide hormones; all amino acid-derived hormones except thyroid hormones).
• Lipid-soluble hormones (thyroid hormones, steroid hormones, eicosanoids).
• The vast majority of hormones are water-soluble.

Water-Soluble Hormones: Function

• Synthesis, release, and transport in blood.
• Mechanisms of action: extracellular receptors.

Water-Soluble Hormone Synthesis

• Amino acids converted to hormones by enzymes (e.g., adrenaline).
• Amino acids made into peptides or proteins (protein synthesis, e.g., insulin).
• Peptide hormones often derived from larger precursors (pre-pro-hormone → pro-hormone → hormone).
• Cleavage of the precursor is tissue/cell-specific.

Water-Soluble Hormone Synthesis & Release

• Water-soluble hormones are pre-made and packaged into vesicles stored in the cytoplasm until released by exocytosis in response to a stimulus (regulated secretion).

Water-Soluble Hormone Transport

• Once released, they are free to travel in the blood throughout the body.
• Peptide hormones are hydrophilic and mix easily with blood plasma.
• Hormones travel until they reach a cell with an appropriate target receptor on the cell surface to which they bind.

Water-Soluble Hormones and Extracellular Receptors

• All water-soluble hormones bind to extracellular (cell-surface) receptors.
• Cellular responses to hormones are mediated by receptors that initiate a complex array of cellular events upon ligand binding.

Cellular Response to Water-Soluble Hormones

• Hormone-mediated activation of its extracellular receptor leads to the activation of intracellular “signaling cascades” resulting in:
  • Fast effects and rapid changes in cell behavior (“non-genomic response”) via rapid modification of pre-existing molecules.
  • Long-term effects and slow changes in cell behavior (“genomic response”) via changes in gene transcription and synthesis of new proteins.

Summary: Water-Soluble Hormones