WEEK 9 REVIEW

  1. Explain the steps involved in the activation of a GPCR, including the role of Gα, Gβ, and Gγ subunits.

    • GPCR activation involves G-proteins, which are heterotrimeric (Gα, Gβ, Gγ).

    • Steps of activation:

      1. Ligand binds to GPCR, causing a conformational change in the receptor.

      2. GDP (inactive) on Gα is replaced with GTP (active) → activates G-protein.

      3. Gα dissociates from Gβγ → both subunits trigger different signaling pathways.

      4. Gα activates or inhibits target enzymes (e.g., adenylyl cyclase, PLC), producing second messengers (e.g., cAMP, IP3, DAG).

      5. Gβγ can modulate ion channels (e.g., opening K+ channels).

      6. Deactivation: GTP is hydrolyzed back to GDP, and Gα reassociates with Gβγ.

  1. Describe how activation of mAChR leads to an outward IK+ in the postsynaptic cell.

    • mAChR (muscarinic acetylcholine receptor) is a metabotropic receptor.

    • When ACh binds, it activates the G-protein.

    • Gβγ subunit directly activates K+ channels (GIRK channels), causing K+ efflux.

    • This hyperpolarizes the postsynaptic cell, making it less likely to fire an action potential.

  1. Describe the biosynthesis and function of endocannabinoids in the nervous system.

    • Endocannabinoids (eCBs) are lipid-based retrograde messengers.

    • Biosynthesis:

      • Unlike classical neurotransmitters, endocannabinoids are synthesized on demand (not stored in vesicles).

      • Two main types:

        1. AEA (anandamide): Synthesized from NAPE-PLD enzyme.

        2. 2-AG (2-arachidonoylglycerol): Synthesized from DAGL enzyme.

    • Functions:

      • Bind to CB1 (CNS) and CB2 (immune system) receptors.

      • Modulate pain, appetite, mood, memory, and motor control.

      • Act as negative feedback regulators in synaptic transmission (reduce neurotransmitter release).

  1. What are the primary differences between the endocannabinoid system and classical neurotransmitter systems?

    • Endocannabinoid System:

      • Retrograde signaling (travels backward from postsynaptic to presynaptic).

      • Lipophilic (not stored in vesicles) → synthesized on demand.

      • Acts locally and is quickly degraded.

    • Classical Neurotransmitter System:

      • Released presynaptically, binds to postsynaptic receptors.

      • Stored in vesicles and released via exocytosis.

      • Can have long-range effects.

  1. Explain the role of CB1 and CB2 receptors in the endocannabinoid system and their localization in the body.

    • CB1 Receptors (CNS & PNS):

      • Found in the brain (hippocampus, cerebellum, basal ganglia).

      • Modulate memory, pain, motor coordination, and mood.

    • CB2 Receptors (Immune System):

      • Found in immune cells (macrophages, microglia).

      • Involved in inflammation and immune response.

  1. How does retrograde signaling work in the context of endocannabinoids, and why is it important for synaptic plasticity?

    • Retrograde signaling: Instead of neurotransmitters being released from the presynaptic neuron, endocannabinoids travel backward from the postsynaptic to the presynaptic neuron.

    • Steps:

      1. Postsynaptic neuron detects high activity (Ca²⁺ influx).

      2. Endocannabinoids (AEA or 2-AG) are synthesized on demand.

      3. They diffuse back to the presynaptic terminal and bind CB1 receptors.

      4. CB1 activation inhibits presynaptic neurotransmitter release, reducing excessive excitation or inhibition.

    • Importance in synaptic plasticity:

      • Short-term synaptic depression: Temporarily reduces neurotransmitter release.

      • Long-term depression (LTD): Reduces synaptic strength over time, contributing to learning & memory.

      • Acts as a protective mechanism against excessive neural activity (e.g., seizures).