Cell Communication

Extracellular Reception
- Receptor protein is a transmembrane protein.
- Signal molecule binds to the extracellular domain.
- There are many kinds of signal molecules that can trigger this pathway.
- The intracellular domain undergoes a conformational change after binding.
- Signal is relayed to downstream participants.
Intracellular Reception
- Receptor protein is located intracellularly.
- Signal molecule must cross the membrane and bind to the intracellular receptor protein.
- Signal molecules must be small and hydrophobic to cross the membrane.
- The signal is also relayed to downstream participants.

Types of Signal Molecules:
- Almost any type of molecule may act as a signal – can be organic or inorganic, large or small, including ions and metals.
- Cellular Origin: Cells/organisms signal one another, applicable to both unicellular and multicellular organisms.
- Environmental Origin: Cells can interpret signals from their environment.
- There are instances of molecular mimicry in signaling.

Process:
- Starts with a signal molecule.
- Involves transmembrane receptor protein, including an extracellular domain and intracellular domain.
- Involves several intermediate participants.
- Results in target proteins triggering a response.

Contact-Dependent:
- Signaling cell communicates directly with target cell through membrane-bound signal molecules.
Paracrine:
- Local mediators signal neighboring cells.
Synaptic:
- Neurons communicate via neurotransmitters at synapses.
Endocrine:
- Endocrine cells release hormones into the bloodstream to affect distant target cells.

Different receptors may trigger different responses to the same signal.
Different cell types may respond differently to similar combinations of signals.
A single cell with multiple receptor types may exhibit multiple responses to a single signal.
The unlimited combinations of signals create a complex signaling "language."

The signal molecule binds to the extracellular domain of a receptor.
The intracellular domain undergoes a conformational change.
This change activates downstream participants ("intracellular mediators").
- These can relay the signal directly or catalyze the synthesis of another small molecule that activates the next protein in the pathway.

Process flow:
- Signal molecule → Receptor protein → Latent gene regulatory protein → Plasma membrane → Cytosol → Scaffold protein → Relay proteins → Integrator proteins → Anchor proteins → Target proteins → Activated gene (final response).

There are three major types of receptors:
1. Ion-Channel Coupled Receptors:
- Also known as transmitter-gated receptors.
1. G-Protein Linked Receptors:
2. Enzyme-Linked Receptors:

This receptor is a 7-pass transmembrane protein
It activates a member of the G-protein family, which functions as molecular switches using their GTPase activity.
G-proteins can receive a wide variety of signal types due to their large family diversity.

G-proteins are predominantly trimeric with three subunits: α, ß, and γ.
The α and γ subunits are tethered to the intracellular leaflet and the α subunit possesses GAP-GEF activity alongside its switch properties.
Activation Process:
- When a signal molecule binds to the extracellular domain of the G-protein linked receptor, the receptor contacts the G-protein.
- The G-protein’s GEF activity facilitates the exchange of GDP for GTP, activating the G-protein.
- The activated G-protein dissociates into subunits, which then contact target proteins to relay the signal.
- The GAP activity of the α-subunit hydrolyzes GTP, inactivating the G-protein, which then reassociates as a trimer.

cAMP serves as a mediator for many processes within the cell.
Cellular [cAMP] balances synthesis by adenyl cyclase and degradation by cAMP phosphodiesterase.
Generally, extracellular signals increase [cAMP] by enhancing the activity of adenyl cyclase.

The α subunit of the activated G-protein stimulates adenyl cyclase, resulting in the conversion of GTP to GDP.
After activation, the α and ßγ subunits reassociate, completing the normal G-protein function.

Elevated cAMP binds to regulatory sites on cAMP-dependent protein kinases (PKA).
The binding activity causes dissociation of the catalytic subunits of PKA leading to activation
Different targets are phosphorylated by the catalytic subunits of various PKA enzymes.

Signal molecule activates adenyl cyclase which then generates cAMP.
cAMP activates PKA, which phosphorylates CREB protein, allowing targeted gene transcription in the nucleus.

G-protein receptors can activate phospholipase C-ß, leading to the generation of two cleavage products:
- Inositol triphosphate (IP3)
- Diacylglycerol

The concentration of Ca2+ in the cytosol is very low compared to extracellular environments.
Ca2+ pumps are found in the plasma membrane, ER membrane, and mitochondrial membrane, creating a strong electrochemical gradient.
When Ca2+ channels open, there is a rapid increase in cytosolic [Ca2+].

Calmodulin is a calcium-binding protein present in all eukaryotic cells.
It functions as a monomeric protein with four Ca2+ binding sites, requiring two or more Ca2+ for activation.
The Ca2+/calmodulin complex can activate various proteins, often by activating kinases.

These receptors respond to extracellular signals that promote
- cell growth, proliferation, and differentiation.
- contribute to cell survival (commonly known as growth factors).
- often signal on substrate triggering changes in cell shape and movement through cytoskeletal changes.
Transcription factors are commonly targeted at the end of this process.

Signaling molecules that diffuse into the cell must be small and hydrophobic (e.g. nitric oxide).
For instance, nitric oxide (NO) serves as a signaling molecule that activates guanyl cyclase.

NO is a prolific signaling molecule synthesized from arginine.
It easily diffuses out of the source cell and into the target cell, where it commonly activates guanyl cyclase.

cGMP mediates numerous and varied cellular processes.
Nitric oxide has a very short lifespan (5-10 seconds), indicating its local action only, which is an important control mechanism for signaling.

The production of nitric oxide is often initiated by acetylcholine, a neurotransmitter released from nerve cells, that triggers cells to synthesize NO.

The process involves acetylcholine activating NO synthase, leading to the production of NO from arginine which diffuses rapidly across the membranes, causing relaxation of smooth muscle cells due to subsequent cyclic GMP generation.