Cellular Communication: Receptor Types

Cellular Communication 4

• Focuses on Receptor Tyrosine Kinases (RTKs), ionotropic receptors, intracellular receptors, correlating receptor mechanisms with cellular response speed, and receptor-mediated endocytosis.

Major Types of Receptors and Signal Transducers

• G protein-coupled receptors activate an intracellular GTP-binding protein (G), regulating an enzyme (Enz) to produce an intracellular second messenger (X).
• Receptor tyrosine kinases activate tyrosine kinase activity by autophosphorylation upon ligand binding.
• Receptor guanylyl cyclase stimulates the formation of cyclic GMP, a second messenger, when a ligand binds to its extracellular domain.
• Adhesion receptors (integrins) bind molecules in the extracellular matrix, changing conformation and interaction with the cytoskeleton.
• Gated ion channels open or close in response to a signal ligand concentration or membrane potential.
• Nuclear receptors allow steroid binding to regulate specific gene expression.

Kinases and Phosphorylation

• Kinases are enzymes catalyzing protein phosphorylation with ATP.
• Phosphorylation usually changes the target protein's function by altering enzyme activity, cellular location, or association with other proteins.
• Phosphorylation can occur by autophosphorylation or by binding to activator/inhibitor proteins.
• Phosphorylation of proteins regulate several cellular pathways.

Protein Kinase Receptors

• Two main types of protein kinase receptors exist.
• One type is Serine/Threonine Kinases, which phosphorylates serine and threonine amino acids and includes MAP kinase, involved in mitoses and cellular differentiation.
• The other type is Tyrosine Kinases, which phosphorylates proteins on tyrosine amino acid residues and includes insulin and growth factor receptors.

Receptor Tyrosine Kinase (RTK)

• RTKs are membrane receptors with intrinsic protein kinase activity, using autophosphorylation.
• RTKs transduce extracellular signals differently than GPCRs.
• RTKs include an extracellular ligand-binding domain and a cytoplasmic face with an enzyme active site, connected by a single transmembrane segment.
• The cytoplasmic domain is a protein kinase that phosphorylates TYR residues.
• Examples of RTKs are receptors for insulin and epidermal growth factors.

Receptor Tyrosine Kinase Example

• Here is an example using an Insulin Receptor:
• Signal molecules bind to receptor tyrosine kinase proteins (inactive monomers)
• This causes dimerization
• The receptors phosphorylate each other
• This attracts the active relay proteins which activate cellular responses

Termination of RTK Signal

• Downregulation is the major regulatory mechanism for RTK signal termination through receptor endocytosis and degradation.
• Receptors and signals can also be terminated by sequestration, inactivation, inhibitory proteins or modulation
• The receptor can also be regulated via phosphorylation state modulation
• Antagonist ligands can inhibit the biological responses mediated by the receptor.

Ionotropic Receptors (Ligand-Gated Ion Channels)

• Electrically excitable cells use ionotropic receptors to convert external signals into electrical signals by changing the membrane potential.
• These receptors are central in nerve conduction, muscle contraction, hormone secretion, and sensory and learning processes.
• Excitability relies on channels and type of ion they pass.
• The channels are signal transducers that regulate inorganic ion movement across the plasma membrane in response to stimuli.
• Channels are gated and activated by binding specific ligands/first messengers like neurotransmitters or hormones.

Ionotropic Receptors Examples

• GABA-A receptors can pass Cl- or HCO3- and are the major inhibitory neurotransmitter in the CNS.
• Nicotinic Acetylcholine receptors can pass Na+, K+, and Ca+2 and typically mediate excitatory neurotransmission.

Nicotinic Acetylcholine (ACh) Receptor

• Nicotinic acetylcholine (ACh) receptor is found at the neuromuscular junction.
• The neuromuscular junction is a synapse between a motor neuron and a muscle fiber.
• The signal causes membrane depolarization, triggering skeletal muscle contraction.

Intracellular Receptors

• Lipophilic ligands utilize intracellular receptors These ligands are carried by transport proteins in the blood plasma and then dissociate to enter target cells
• Small hydrophobic signal molecules diffuse directly across the plasma membrane into the target cells.
• Intracellular receptors (in the cytoplasm OR in the nucleus) act as transcription regulators.
• Examples of these lipophilic ligands includes steroid hormones, thyroid hormones, retinoids, and vitamin D.

Intracellular Receptors ARE Receptors and Effectors of the Ligands

• Ligands bind to their intracellular receptor proteins, altering the ability of these proteins to control the transcription of specific genes.

Speed of Cellular Response

• Ligand-gated ion channels' response time is in milliseconds such as Cholinergic nicotinic receptors
• G protein-coupled receptors' response time is in seconds such as a and ẞ adrenoceptors, and muscarinic cholinergic receptors.
• Enzyme-linked receptors' response time is in minutes such as insulin and cytokine receptors.
• Intracellular receptors' response time is in minutes to hours such as steroid receptors.

Receptor Mediated Endocytosis

• Initiated when receptors are activated by the signal
• Membrane associated protein CLATHRIN is essential for this mechanism

Endocytosis of cholesterol via LDL: An Example:

• A molecule binds to a protein receptor
• This leads to the molecules moving to a clathrin coated pit
• The pit and cell membrane start to fold inwards
• This forms a coated vesicle
• The vesicle fuses with an endosome
• The receptors and molecules separate.