9. Cellular Receptors: Types and Properties

• Receptors are responsible for receiving and transducing signals within the body

Receptors for Chemical Messengers

• Intracellular receptors such as the nucleus or cytosol are for substances soluble in fat, with products of intracellular metabolism
• Examples of substances include steroid hormones, T-hormones, fatty acids, cholesterol, and prostaglandins
• Cell membrane receptors are for substances insoluble in lipids
• Examples of substances include amines, amino acids, peptides, eikosanoids, and purines

Receptor Properties

• Specificity relates to the receptor's ability to bind to only one type of messenger or structurally related messengers
• Affinity describes the strength with which a messenger binds to a receptor
• Saturation involves the degree to which receptors are occupied by messengers

Intracellular Receptors

• Cytoplasmic receptors include steroid hormones, vitamin D, and prostaglandins
• Nuclear receptors include T-hormones

Cytoplasmic Receptors Process

• Ligands diffuse across the membrane and bind to their receptor
• Accompanied proteins then dissociate
• Dimerization of complexes R-H occurs, followed by transport to the nucleus
• R-H binds to the HRE sequence of DNA along with coactivators and RNA polymerase
• Transcription is activated, leading to mRNA synthesis
• mRNA diffuses into the cytoplasm, activating translation and protein synthesis

Nuclear Receptors Process

• Ligands diffuse across the membrane
• Ligands bind to the nuclear receptor in a heterodimer with RXR, bound to HRE
• Corepressors are released, and coactivators bind with RNA polymerase on the complex
• Transcription is activated, leading to mRNA synthesis
• mRNA diffuses into the cytoplasm
• Translation initiates and protein synthesis occurs

Membrane Receptors

• The extracellular message is transferred into the intracellular environment through diffusion or synthesis of the second messenger
• The second messenger mediates various immediate intracellular events and induces long-term changes
• Kinases mediate most events by phosphorylating target proteins like pumps, enzymes, channels, and transcription factors

Second Messengers

• Includes small, diffusible molecules that facilitates information transfer from the ECF into the ICF
• Cyclic nucleotides include: cyclic adenosine monophosphate or cAMP (NE, EPI, ADH), and cyclic guanosine monophosphate or cGMP (ANP)
• Derivatives of membrane lipids include diacylglycerol and inositol trisphosphate (NE, ACh, ADH)
• Others include: Ca2+, gases (NO/CO/H2S), and ROS/RNS

Phospholipases

• Are involved in the cleavage of phospholipids, generating second messengers

Signaling Pathways

• cAMP utilizes adenylyl cyclase (AC) which converts ATP into cAMP, which activates protein kinase A and phosphorylates downstream proteins.
• cAMP is degraded by phosphodiesterase (PDE) forming AMP
• Phospholipase C (PLC) splits phosphatidylinositol-4,5-bisphosphate (PIP2) from the membrane, producing inositol-1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG)
• DAG activates protein kinase C (PKC) and IP3 releases Ca2+ from the ER
• cGMP is bound to the inner opening of the Na+ channel in photoreceptors
• Light activates phosphodiesterase (PDE), degrading cGMP which closes the channel
• Prostaglandins, vascular effects, and inflammation are regulated by phospholipase A2, cyclooxygenase, and arachidonic acid

Membrane Chemoreceptors

• Include receptor channels, G-protein coupled receptors, and catalytic receptors

Receptor Channels: Ligand-Gated

• Ligand binding to the receptor triggers a conformational change which opens the channel and facilitates ion diffusion
• Ion diffusion results in a change in membrane potential (IPSP, EPSP) and cellular response
• GABA, glycine, glutamic acid, Ach, serotonin, and ATP are common receptors

G-Protein Coupled Receptors

• Composed of three subunits: alpha, beta, and gamma
• Alpha subunits display GTP-ase activity and regulate the synthesis of the second messenger
• Common types of receptors are Gas, Gai, and Gaq
• Following GTP binding, beta and gamma subunits dissociate from the G-protein, activating processes leading to second messenger formation
• Ligand binds to the receptor and the complex R-L binds G-protein
• G-protein exchanges GDP for GTP
• G-protein with GTP dissociates into alpha and beta-gamma subunits
• The subunits activate the enzyme producing the second messenger
• After GTP splitting, the alpha-GDP complex dissociates from the enzyme.
• The second messenger is then degraded by an enzyme

Catalytic Receptors

• Includes enzymes or enzyme complexes which are mostly individual transmembrane proteins
• Frequently form dimers or oligomers following activation
• Differentiates, proliferates and matures the cells
• Involved in apoptosis, necrosis, and inhibits growth and maturation

Catalytic Receptor Types

• Guanylate cyclase
• Serine/threonine kinases
• Tyrosine kinases
• Receptors coupled to tyrosine kinases
• Phosphotyrosine phosphatases

Guanylate Cyclases

• Includes natriuretic peptides like ANP, BNP, and CNP
• ANP is released from atrial cardiomyocytes during atrial distension and results in vasodilatation and natriuresis
• BNP is isolated from the porcine brain and is a marker of heart failure
• CNP is isolated from the porcine brain and results in vasodilation
• Receptor directly catalyzes conversion of GTP to cGMP

Guanylyl Cyclases Functions

• Regulation of blood pressure and volume
• Inhibition of cardiomyocyte growth
• Water and ion transport
• Ossification
• Pheromone detection

Serine-Threonine Kinases

• First cloned in 1991
• Ligands such as activins, inhibins, myostatin, bone morphogenetic protein, and TGF-β
• Receptor phosphorylates itself on serine and threonine residues

Functions of Ser/Thr Kinases (STK)

• Muscle and Bone development
• Regulation of hormone secretion
• Proliferation
• Angiogenesis
• Apoptosis

Tyrosine Kinases

• Research began in the 60th century and the structure was revealed in 1991
• Major ligands include Insulin, nerve growth factors such as NGF or neurotrophins, and epidermal growth factor (EGF)
• Receptor phosphorylates itself on tyrosine residues

Insulin

• Concerned with intermediary metabolism, growth, and ion balance, impacting the insulin receptor substrate

Neurotrophic Growth Factors

• NGF was discovered in 1951, isolation began in 1956, and neurotrophic peptides were found in 1986
• Plays a role in essential neuronal growth and survival, secreting from target organs

Receptors Coupled to Tyrosine Kinases

• Includes ligands such as prolactin and other hormones like growth hormone, erythropoietin, macromolecules or products of microorganisms - Toll-like receptors, and tumor necrosis factor (TNF-α)
• Kinases JANUS/ transcription factors STAT which act as signal transducers and activators of transcription
• Receptor is coupled to tyrosine kinase, which phosphorylates it

Phosphotyrosine Phosphatases

• Research began after 2000
• Includes ligands such as hyaluronic acid and proteins of extracellular matrix, however, these are frequently unknown
• The intracellular substrate is a kinase that becomes prepared for activation by dephosphorylation
• Receptor removes phosphate from other proteins

Down-and Up-Regulation

• Down-regulation results in decreased total receptors for a ligand and occurs in response to a chronic increase in EC concentration of the ligand
• Up-regulation results in increased total receptors for a ligand and occurs in response to a chronic reduction in EC concentration of messenger

Other Regulations

• Internalization is receptor-mediated endocytosis, which decreases the number of receptors, down-regulating or recycling the receptor
• Desensitization results in a decreased receptor response to a messenger, due to high signaling molecule concentration and uncoupling the receptor from the signaling cascade