Structure and Function

Intercellular Communication

Intercellular communication refers to the exchange of information between cells, enabling them to coordinate their activities and maintain homeostasis within tissues, organs, and the entire organism. This communication is essential for processes such as development, immune responses, and maintaining tissue structure and function. There are several mechanisms by which cells communicate with each other:

Paracrine Signaling**
- Involves signaling molecules (e.g., cytokines, growth factors) that are secreted by one cell and affect nearby target cells.
- Example: Synaptic transmission in neurons, where neurotransmitters influence neighboring cells.

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### 3. **Autocrine Signaling**
- A cell secretes signaling molecules that bind to its own receptors, influencing its behavior or activity.
- Example: Cancer cells often use autocrine signaling to stimulate their growth.

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### 4. **Endocrine Signaling**
- Hormones are released into the bloodstream by endocrine glands and travel to distant target cells.
- Example: Insulin secreted by the pancreas affecting glucose uptake in muscles and liver.

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### 5. **Juxtacrine Signaling**
- Requires physical contact between cells. A signal molecule is presented on the surface of the signaling cell and interacts with receptors on an adjacent cell.
- Example: Notch signaling during embryonic development.

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### 6. **Exosomes and Extracellular Vesicles**
- Cells release vesicles containing proteins, lipids, and nucleic acids (like mRNA or miRNA) into the extracellular environment, which can then be taken up by other cells.

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### 7. **Electrical Signals**
- In excitable tissues like neurons and muscles, action potentials and electric currents allow rapid communication.

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### Applications and Importance:
- **Developmental Biology**: Regulates cell differentiation and tissue formation.
- **Immunology**: Coordinates the immune response against pathogens.
- **Cancer**: Dysregulated communication contributes to tumor growth and metastasis.
- **Regenerative Medicine**: Understanding these mechanisms aids in tissue engineering and stem cell therapies.

Would you like more detail on any specific mode of intercellular communication?

Five illustrations depict various modes of intercellular communication. The first illustration shows the neural mode of intercellular communication. A neuron with a cell body, dendrites and an axon is shown, the axon terminates to form a synapse releasing neurotransmitters that communicate with the post synaptic cell. The second illustration shows the endocrine mode of intercellular communication. It shows three cells stacked one on the top of the other, and a blood capillary running close to these cells. Peptide hormones are released from the storage vesicles of the cells; these peptide hormones diffuse through the blood vessel wall into the blood circulation. The third illustration shows the neuroendocrine mode of intercellular communication. A neuron with a cell body, dendrites and an axon is shown. Next to the distal end of the axon is a blood vessel. Diffusion of chemical transmitter from the axon into blood occurs. The fourth illustration shows the paracrine mode of intercellular communication. Four cells are shown stacked one above the other. The hormone diffuses locally to reach target cell. The last illustration depicts the autocrine mode of intercellular communication. It shows a cell that secretes a hormone that acts on the same cell.

Direct communication. During cell-cell recognition or contact inhibition of cell division, signal transduction may require temporary physical contact.

These areas of contact are often marked by specialized junctional complexes . Some components of junctional complexes are specialized for attachment (physical communication), and others (gap junctions) provide cytoplasmic channels that transmit electric and chemical signals.
Indirect communication. Signals are also transmitted from cell to cell even when they are not in contact. In paracine communication, the signal traverses a short distance (e.g., hormones, growth factors, or other signal molecules produced by one cell type have effects on another in the same tissue). In endocrine and neural communication, the signal travels farther (e.g., when hormone-producing cells in one tissue elicit responses from targets in others).
Cells communicate with each other by sending signaling molecules to each other. The cell that synthesizes and releases the chemical is the signaling cell and the intended receiver cell is the target cell. In order to receive the signal, the target cell must have a receptor molecule to which the signaling molecule can bind. Signaling molecules can be neurotransmitters (released into synaptic clefts) and hormones. Hormones are of three types: endocrine, which use the bloodstream to be delivered to their target cells; paracrine, which is released into the extracellular space to a target cell in the near vicinity; and autocrine, which is released into the extracellular space to activate the signaling cell itself. The two major types of signaling molecules are:
1. Lipid-soluble signaling molecules or small nonpolar molecules (e.g., NO) that penetrate the cell membrane and bind to receptors within the cytoplasm or inside the nucleus, activating intracellular messengers. Examples include hormones that influence gene transcription.
2. Hydrophilic signaling molecules bind to and activate cell surface receptors (as do some lipid-soluble signaling molecules) and have diverse physiologic effects (see Chapter 11). Examples include neurotransmitters and numerous hormones (e.g., serotonin, thyroid-stimulating hormone, insulin).

Receptors (protein molecules) bind to specific ligands, which activate numerous cellular processes; There are two types.

Cell-Surface

Intracellular

Also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules.

An integral protein is a protein molecule (or assembly of proteins) that is permanently attached to the biological membrane.

Cell-surface receptors convert an extracellular signal into an intracellular signal.

Three general categories of cell-surface receptors include: ion-channel, G-protein, and enzyme-linked protein receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through.

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein, which then interacts with either an ion channel or an enzyme in the membrane.

Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illness. In cholera, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body that can lead to potentially fatal dehydration.

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme.

This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Each cell-surface receptor has three main components: an external ligand-binding domain (extracellular domain), a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Internal receptors

Intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell's DNA into a sequence of amino acids that ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, binds to specific regulatory regions of the chromosomal DNA, and promotes the initiation of transcription . Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Intracellular Receptors

Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.

Intracellular receptors are located in the cytoplasm of the cell and are activated by hydrophobic ligand molecules that can pass through the plasma membrane.

Cell signaling is the transmission of molecular signals from a cell's exterior to its interior.

It is initiated by cell-surface receptors.

Cell signaling encompasses responses to extracellular signals (hormones, neurotransmitters, etc.) and how they produce an intracellular response.

In addition to endogenous agents, many drugs and environmental agents use these same mechanisms to produce their most important effects.

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Cell Proliferation and Cycle Control

Apoptosis

Oncogenes and Tumor Suppressor Genes

Metastasis Angiogenesis Tumor Invasion Cell Adhesion Cell Migration Signal Transduction and Growth Regulation Molecular Profiling Translation Applications Transgenic and Knockout Models.

MCBP 743 - Cellular Signaling During Development
This course is designed to build on the Regulation of Gene Expression, Biomembranes, Receptors and Signaling and Systems Biology units of the first year curriculum for Ph.D. and complement ongoing Department-specific seminars and journal clubs. Cellular Signaling during development will provide the students with an indepth look at ongoing research in the field of developmental biology with a strong focus on the signaling networks that control these important processes. It will allow for a broad scope of understanding of the techniques, theories and practices involved in the delineation of cellular signaling in complex systems. Offered every Spring Semester.
Credits: 3.00
Director: Robin C. Muise-Helmericks, Ph.D.

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MCBP 748/BMB 748 Lipids in Pathobiology
This multidisciplinary course addresses biochemical, applied, and translational approaches to the study of lipids. The course is composed of three main sections: lipid biosynthesis, lipid signaling, and lipids and disease. The first section is a comprehensive treatment of nomenclature and synthesis of major lipid classes including glycerophospholipids, sphingolipids, and sterols, as well as methodology for lipid study. The second section addresses roles of bioactive members of these lipid classes in regulation of cell signaling and downstream events. The third section is largely translational, with many lectures on human diseases that involve the lipids and signaling pathways discussed. This course contains a brief hands-on laboratory segment. This course is open this to graduate students, residents, postdocs, and third and fourth medical students.
Credits: 3
Director: Samar M. Hammad (Co-Director: Ashley Cowart)
Offered every two years in the Spring

Intracellular Receptors

Intracellular receptors are located in the cytoplasm of the cell and are activated by hydrophobic ligand molecules that can pass through the plasma membrane.

Cell-surface receptors

Cell-surface receptors bind to an external ligand molecule and convert an extracellular signal into an intracellular signal.
Three general categories of cell-surface receptors include: ion-channel, G-protein, and enzyme-linked protein receptors.
Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through.
G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein, which then interacts with either an ion channel or an enzyme in the membrane.
Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme.

integral protein
a protein molecule (or assembly of proteins) that is permanently attached to the biological membrane

Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illness. In cholera, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body that can lead to potentially fatal dehydration.

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Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligands. There are two types of receptors: internal receptors and cell-surface receptors.

Internal receptors

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell's DNA into a sequence of amino acids that ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, binds to specific regulatory regions of the chromosomal DNA, and promotes the initiation of transcription . Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Intracellular Receptors

Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.

Cell-Surface Receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Each cell-surface receptor has three main components: an external ligand-binding domain (extracellular domain), a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion Channel-Linked Receptors

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein's structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through .

Gated-Ion Channels

Gated ion channels form a pore through the plasma membrane that opens when the signaling molecule binds. The open pore then allows ions to flow into or out of the cell.

G-Protein Linked Receptors

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane. All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly-revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the α subunit and the β subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. Later, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the β subunit is deactivated. The subunits reassociate to form the inactive G-protein, and the cycle starts over .

G-proteins

Heterotrimeric G proteins have three subunits: α, β, and γ. When a signaling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the α subunit is exchanged for GTP. The β and γ subunits dissociate from the α subunit, and a cellular response is triggered either by the α subunit or the dissociated β pair. Hydrolysis of GTP to GDP terminates the signal.

Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme or the enzyme-linked receptor has an intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane and activates the enzyme, which sets off a chain of events within the cell that eventually leads to a response. An example of this type of enzyme-linked receptor is the tyrosine kinasereceptor. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules. Signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors, which then dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors and can then transmit the signal to the next messenger within the cytoplasm.

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A scientist discovers that the addition of a new hydrophobic drug to a culture of cancer cells results in increased transcription of a specific gene. Based on your knowledge of receptors, which type of receptor is most likely activated?

KEY TERM REFERENCE

SOURCES

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Source: Boundless. “Types of Receptors.” Boundless Biology. Boundless, 26 May. 2016. Retrieved 30 Oct. 2016 from https://www.boundless.com/biology/textbooks/boundless-biology-textbook/cell-communication-9/signaling-molecules-and-cellular-receptors-83/types-of-receptors-381-11607/

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Cell regulation encompasses the functions cells carry out to maintain homeostasis, in particular their responses to extracellular signals (hormones, neurotransmitters, etc.) and how they produce an intracellular response. In addition to these endogenous agents, many drugs and environmental agents use these same mechanisms to produce their most important effects.

Research Fronteir:

[Numerous research opportunities exist within this program ranging from studies exploring new cell signaling mechanisms, to those examining basic the aberrant signaling mechanisms associated with disease states.

Cell Regulation Course Descriptions

MCBP-725D/PCOL 747 Topics in Cancer Research
Two presentation formats will be used for the course. Initially, a faculty member will introduce and direct all students in the discussion of selected literature concerning a single topic. Subsequent topics will be presented by individual students in Journal Club style. Each student will have two opportunities to present selected topics during the course and will be active discussants when other students present. Topics to be covered include: Cell Proliferation and Cycle Control Apoptosis Oncogenes and Tumor Suppressor Genes Metastasis Angiogenesis Tumor Invasion Cell Adhesion Cell Migration Signal Transduction and Growth Regulation Molecular Profiling Translation Applications Transgenic and Knockout Models. Offered in Fall Semester of alternate years.
Prerequisites: None
Credits: 3 (Pass/Fail)
Steve Rosenzweig, Ph.D., and Dennis Watson, Ph.D.

MCBP 743 - Cellular Signaling During Development
This course is designed to build on the Regulation of Gene Expression, Biomembranes, Receptors and Signaling and Systems Biology units of the first year curriculum for Ph.D. and complement ongoing Department-specific seminars and journal clubs. Cellular Signaling during development will provide the students with an indepth look at ongoing research in the field of developmental biology with a strong focus on the signaling networks that control these important processes. It will allow for a broad scope of understanding of the techniques, theories and practices involved in the delineation of cellular signaling in complex systems. Offered every Spring Semester.
Credits: 3.00
Director: Robin C. Muise-Helmericks, Ph.D.

MCBP 748/BMB 748 Lipids in Pathobiology
This multidisciplinary course addresses biochemical, applied, and translational approaches to the study of lipids. The course is composed of three main sections: lipid biosynthesis, lipid signaling, and lipids and disease. The first section is a comprehensive treatment of nomenclature and synthesis of major lipid classes including glycerophospholipids, sphingolipids, and sterols, as well as methodology for lipid study. The second section addresses roles of bioactive members of these lipid classes in regulation of cell signaling and downstream events. The third section is largely translational, with many lectures on human diseases that involve the lipids and signaling pathways discussed. This course contains a brief hands-on laboratory segment. This course is open this to graduate students, residents, postdocs, and third and fourth medical students.
Credits: 3
Director: Samar M. Hammad (Co-Director: Ashley Cowart)
Offered every two years in the Spring

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Ion Channel-Linked Receptors

Gated-Ion Channels

Gated ion channels form a pore through the plasma membrane that opens when the signaling molecule binds. The open pore then allows ions to flow into or out of the cell.

G-Protein Linked Receptors

G-proteins

Enzyme-Linked Receptors

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See: http://en.wikipedia.org/wiki/Cell_surface_receptor

How do the tyrosine kinase receptors transduce their messages?

As depicted in Figure 8-3 , binding of peptide hormone to the extracellular domain of the receptor initiates a signal transduction cascade by promoting autophosphorylation of the kinase receptor and subsequent phosphorylation of downstream target proteins, thereby activating or inhibiting these proteins.

Figure 8-3

Mechanism of activation of a tyrosine kinase receptor.

(From Meszaros JG, Olson ER, Naugle JE, et al: Crash Course: Endocrine and Reproductive Systems. Philadelphia, Mosby, 2006.)

7 How do the ligand-gated ion channels work?

Activation of ligand-gated ion channels results in an influx (or efflux) of ions into (or out of) the cell. The nicotinic receptor on skeletal muscle is an example of such a receptor. Binding of acetylcholine to this receptor results in an influx of principally sodium ions into the cell.

8 How do the G proteins transduce their signals?

Binding of hormone/agonist to G protein–coupled receptors causes an αβγ subunit complex to exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Once GTP is bound to the subunit complex, it dissociates into the α subunit and a separate βγ subunit. These dissociated subunits then activate or inhibit enzymes (adenylate cyclase, phospholipase) and ion channels (Ca 2+ channels) ( Fig. 8-4 ).

Figure 8-4

Signal transduction by G proteins. βARK, β-adrenergic receptor kinase; GAP, GTPase-activating protein; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanosine triphosphate; Pi, inorganic phosphate, PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLCβ, phospholipase Cβ; Raf1, effector protein; Ral GDS, Ras-related GTPase guanine nucleotide dissociation stimulator; RTK, receptor tyrosine kinase.

(From Mann DL: Heart Failure: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 2004.)

Note: Adenylate cyclase synthesizes cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), and the cAMP activates various target proteins. G s receptors stimulate adenylate cyclase, whereas G i receptors inhibit adenylate cyclase.

G proteins are a five-star topic on boards. Study the pathways for G s , G i , and G q signaling depicted in Figure 8-4 . You should know the details of these pathways, including the predominant cellular changes that occur with activation of each protein (e.g., cyclic adenosine monophosphate [cAMP] increase with G s activation, intracellular [Ca 2+ ] increase with G q activation).