4.0 Cell-to-Cell Communication: Signal Reception and Transduction
In multicellular organisms, the coordination of cellular activities is essential for survival and is achieved through sophisticated cell-to-cell communication. Signaling cells secrete molecules that bind to specific receptors on target cells. The range of this communication varies: endocrine signaling acts on distant targets via the bloodstream, paracrine signaling affects nearby cells, and autocrine signaling acts on the same cell that released the signal. The nature of the signal also matters; lipid-soluble molecules may penetrate the membrane to bind intracellular receptors, while hydrophilic molecules typically bind to cell-surface receptors.
4.1 Principles of Membrane-Mediated Signaling
A typical membrane receptor is an integral glycoprotein with three distinct domains: an extracellular domain with a binding site for the signaling molecule, a transmembrane domain that anchors it within the lipid bilayer, and an intracellular domain that interacts with downstream components to transduce the signal. Membrane receptors perform several key functions:
- They control the permeability of the plasma membrane by regulating ion channels.
- They regulate the entry of specific molecules into the cell.
- They bind the extracellular matrix to the cytoskeleton via integrin proteins.
- They act as transducers, translating the binding of an extracellular ligand into an intracellular response, often via second messenger systems.
- They permit pathogens that mimic normal ligands to enter cells.
4.2 Classification of Membrane Receptors
Membrane receptors are broadly classified into three major families based on their structure and mechanism of action.
- Channel-Linked Receptors: In this system, the receptor itself is an ion channel. The binding of a signaling molecule (ligand) directly causes the channel’s gate to open or close, altering the flow of ions across the membrane. The quintessential example is the nicotinic acetylcholine receptor at the neuromuscular junction, which opens to allow Na⁺ influx upon binding acetylcholine, leading to muscle contraction. The clinical relevance of these receptors is underscored by the action of some snake venoms, which contain toxins that inactivate these receptors, causing paralysis.
- Catalytic Receptors: These are typically single-pass transmembrane proteins whose intracellular domain possesses intrinsic enzymatic activity, usually as a protein kinase. When a ligand binds to the extracellular domain, the kinase activity of the intracellular domain is activated. Key examples include receptors for insulin and various growth factors, which initiate phosphorylation cascades that regulate metabolic pathways and cell division.
- G Protein-Linked Receptors: This is the largest and most complex family of cell-surface receptors. After a ligand binds, the receptor is activated and interacts with a heterotrimeric G protein located on the cytoplasmic face of the membrane. This G protein consists of three subunits: α, β, and γ. Activation causes the G protein to exchange GDP for GTP, leading to its dissociation or conformational change, which in turn activates target proteins like enzymes or ion channels. This interaction frequently leads to the generation of intracellular second messengers, such as cyclic AMP (cAMP) or Ca²⁺, which amplify and propagate the signal within the cell. The physiological importance of this system is highlighted by pathogens like Vibrio cholerae, whose toxin irreversibly activates Gs proteins, leading to excessive cAMP production and life-threatening diarrhea.
The diverse functions of heterotrimeric G proteins are critical for cellular regulation, as summarized in the table below.
| Type | Function | Resulting Cellular Effect |
| Gs | Activates adenylate cyclase | Activation of protein kinases via cAMP |
| Gi | Inhibits adenylate cyclase | Protein kinases remain inactive |
| Gq | Activates phospholipase C | Influx of Ca²⁺ into cytosol and activation of protein kinase C |
| Go | Opens K⁺ channels, closes Ca²⁺ channels, and inhibits adenylate cyclase | Influx of K⁺ and limited Ca²⁺ movement |
| Golf | Activates adenylate cyclase in olfactory neurons | Opens cAMP-gated Na⁺ channels, initiating nerve impulse |
| Gt | Activates cGMP phosphodiesterase | Hyperpolarization of rod cell membrane |
| G12/13 | Activates Rho family GTPases | Regulates cytoskeleton assembly by controlling actin formation |
It is also important to distinguish these heterotrimeric G proteins from monomeric (low-molecular-weight) G proteins. These are small, single-chain proteins, with subtypes resembling Ras, Rho, Rab, and ARF proteins, that are involved in regulating processes such as cell proliferation, differentiation, and vesicular traffic.
The proper functioning and localization of these intricate signaling complexes depend on the structural stability provided by the membrane’s association with the underlying cytoskeleton.