Cellular Messaging and Signaling

Importance of Cellular Messaging

• Allows cells to respond to environmental cues and changes.
• Allows cells to communicate with one another to support a multicellular organism.

Types of Cell-to-Cell Signaling (Defined by Distance)

• Direct Contact
  • Direct intracellular
  • Contact dependent
• Short Distance
  • Autocrine
  • Paracrine
• Long Distance
  • Endocrine

Three Stages of Cell Signaling

• The number of chemical messengers and proteins involved in a cell signal are massive.
• These components can be mixed and matched to produce a variety of signals.
• There is a basic underlying structure

Reception

• A signaling molecule binds to a receptor protein, causing it to change shape.
• The binding between a signal molecule (ligand) and receptor is highly specific.
• A shape change in a receptor is often the initial transduction of the signal (i.e., transfers it across the plasma membrane).
• Most signal receptors are plasma membrane proteins:
  • G protein-coupled receptors
  • Enzyme-linked receptors
  • Ion channel receptors
• Intracellular receptors (not plasma membrane proteins)

G-Protein Coupled Receptors

• Activated receptors bind to G-proteins.
• Causes the release of GDP and binds GTP.
• Free α-subunit interacts with other downstream signaling molecules.

Enzyme-Linked Receptors

• Once the extracellular domain binds a signal, the intracellular domain becomes a functional catalyst.
• Most receptors are protein kinases.
  • Receptor tyrosine kinase can trigger multiple transduction steps.

Ligand-Gated Ion Channels

• When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as $Na^+$ or $Ca^{2+}$, through a channel in the receptor.

Intracellular Receptors

• Found in the cytoplasm or nucleus of target cells.
• Small or hydrophobic chemical messengers readily cross the membrane.
• The activated hormone-receptor complex acts as a transcription factor, turning on specific genes.

Transduction

• Cascades of molecular interactions relay signals from receptors to target molecules in the cell.
• Signal transduction usually involves multiple steps.
• Multistep pathways can greatly amplify a signal and provide opportunities for coordination and regulation of the cellular response.
• A receptor activates another protein, which activates another, and so on, until the protein producing the response is activated.
• At each step, the signal is transduced into a different form, usually a shape change in a protein.
• Types:
  • Phosphorylation Cascades
  • Second Messengers

Phosphorylation Cascades

• Phosphorylation and dephosphorylation of proteins is a widespread cellular mechanism for regulating protein activity.
• Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation.
  • Turns on or activates protein.
• Protein phosphatases rapidly remove the phosphates from proteins, a process called dephosphorylation.
  • Turns off or deactivates proteins.

Second Messengers

• Creation of a secondary diffusible signaling molecule inside the cell.
• The extracellular ligand is the "first messenger."
• Small, nonprotein, water-soluble molecules.
• Examples:
  • cAMP
  • $IP_3$ and $Ca^{2+}$

Second Messenger: Cyclic AMP

• Cyclic AMP (cAMP) is one of the most widely used second messengers.
• cAMP activates protein kinase A, which is an enzyme capable of activating other cellular proteins.

Second Messenger: IP3/Ca2+

• Calcium Ions and Inositol Triphosphate ($IP_3$)
• Calcium ions ($Ca^{2+}$) act as a second messenger in many pathways.
• $Ca^{2+}$ can function as a second messenger because its concentration in the cytosol is low.

Second Messenger: IP3/Ca2+

• Production of $IP_3$ leads to increases in cytoplasmic $Ca^{2+}$ levels, which turn on other proteins.
• $PIP<em>2$ is cleaved, leading to diffusible $IP</em>3$ and membrane-bound DAG.

Response

• Cell signaling leads to the regulation of transcription or cytoplasmic activities.
• There are numerous types of cellular responses.
• The response is determined by the proteins activated by the transduction step.
• There are two general categories of response:
  • Cytoplasmic
  • Nuclear

Cytoplasmic Responses

• Regulate the activity of enzymes.
• Opening or closing of an ion channel in the plasma membrane or a change in cell metabolism.
• Signaling pathways can also affect the overall behavior of a cell; for example, a signal could lead to cell division.

Nuclear Responses

• Synthesis of new proteins or enzymes.
• Turn on or off specific genes.
• The final activated molecule in the signaling pathway may function as a transcription factor.