Cell Communication

G Protein-Linked Receptors

  • Definition: A family of receptors whose activation is initiated by ligand binding, which causes conformational changes and activates G proteins.

  • Function: G proteins are guanine-nucleotide binding proteins involved in cellular signaling.

Structure of G Protein-Linked Receptors

  • Common Features:

    • Similar structure but varied amino acid sequences.

    • Form seven transmembrane helices with alternating cytosolic and extracellular loops.

    • Extracellular portion features unique messenger-binding sites.

Regulation of G Protein-Linked Receptors

  • Phosphorylation:

    • Activation leads to phosphorylation of amino acids in the cytosolic domain by G Protein-Coupled Receptor Kinases (GRKs).

    • Phosphorylated receptors bind arrestin, inhibiting receptor function.

G Protein Functionality

  • Switch Mechanism: G proteins operate as molecular switches, active when bound to GTP (on state) and inactive when bound to GDP (off state).

    • Process:

    1. Ligand binding induces receptor conformational change.

    2. G protein releases GDP and binds GTP.

    3. Subunits separate to activate target proteins, initiating signaling.

    4. Hydrolysis of GTP leads to its inactivation.

Cyclic AMP (cAMP) as a Second Messenger

  • Formation:

    • Synthesized from ATP by adenylyl cyclase, which is activated by Gs protein. Inhibition occurs through Gi proteins.

  • Functions:

    • cAMP targets Protein Kinase A (PKA), regulating various cellular functions by phosphorylating proteins on serine (Ser) or threonine (Thr) residues.

Examples of Functions Regulated by cAMP

Function

Target Tissue

Hormone

Glycogen Degradation

Muscle, Liver

Epinephrine

Fatty Acid Production

Adipose

Epinephrine

Increase Heart Rate, Blood Pressure

Cardiovascular

Epinephrine

Water Reabsorption

Kidney

Antidiuretic Hormone

Bone Resorption

Bone

Parathyroid Hormone

IP3 and Diacylglycerol in Signaling

  • Activation:

    • Ligand binding stimulates Gq protein, activating phospholipase C (PLC), which produces inositol triphosphate (IP3) and diacylglycerol (DAG).

  • Mechanism:

    • IP3 binds to calcium channels, promoting calcium release into the cytosol, enabling signaling by activating protein kinase C (PKC).

Calcium's Role in Signaling

  • Key Functions:

    • Regulates diverse cellular activities, maintained by calcium ATPases to keep cytosolic calcium low.

    • Releases through calcium channels or ER storage, contributing to rapid signaling responses.

Receptor Tyrosine Kinases (RTKs)

  • Structure: Comprise one transmembrane segment with extracellular ligand-binding domain and cytosolic tyrosine kinase domain.

  • Activation: Ligand binding triggers receptor dimerization and autophosphorylation, recruiting adaptor proteins to initiate downstream signaling.

Signal Transduction Cascade via RTKs

  • Ras and MAP Kinase Pathway:

    • Activated RTK recruits proteins like GRB2, leading to Ras activation, which then activates various signalling pathways influencing cell growth and differentiation.

Insulin Signaling

  • Mechanism:

    • Insulin binding to RTK dimerizes receptors and activates signaling pathways via IRS-1.

    • Stimulates glucose uptake through GLUT4 translocation and glycogen production via Akt activation.

Steroid Hormone Receptors

  • Functionality:

    • These receptors mediate action of steroid hormones by entering the cell and triggering transcription activation of target genes.

    • Hormone binds receptor, releasing heat shock proteins, leading to gene transcription regulation in the nucleus.