Metabotropic receptors

Structure and Signaling Cycle of the Receptor

The protein chain of metabotropic receptors spans the cell membrane seven times. On the inner side of the cell, the receptor contacts the G protein—a complex consisting of three subunits (α, β, and γ). These proteins get their name from their ability to bind guanine nucleotides.

The signal transduction cycle consists of several stages:

1. Resting state: the receptor is free, with no ligand present. A key marker of the inactive state is that the α-subunit of the G protein is non-covalently bound to a GDP (guanosine diphosphate) molecule.
2. Activation: an agonist binds to the receptor, changing its conformation. GDP on the α-subunit is replaced by GTP (guanosine triphosphate).
3. Signal transduction: the active "α-subunit + GTP" complex detaches from the receptor and the βγ-subunits, after which it travels to effector proteins (enzymes or ion channels).
4. Termination: due to its intrinsic GTPase activity, the α-subunit hydrolyzes GTP back into GDP. The system returns to its initial resting state.

Adenylyl cyclase system (Gs and Gi proteins)

The most thoroughly studied signal transduction mechanism involves the membrane-bound enzyme adenylyl cyclase. The active G protein causes this enzyme to hydrolyze ATP, producing a secondary messenger—cAMP (cyclic adenosine monophosphate). This messenger activates specific cAMP-dependent protein kinases, which phosphorylate cellular proteins, altering their functions.

The ultimate effect depends on the type of G protein:

• Gs proteins stimulate the activity of adenylyl cyclase. An example is the activation of myocardial β1-adrenergic receptors by the sympathetic nervous system. cAMP levels rise, protein kinases phosphorylate calcium channels, and calcium enters the cell more actively. Result: increased sinus node automatism and elevated heart rate.
• Gi proteins inhibit adenylyl cyclase. M2 cholinergic receptors act via these proteins (parasympathetic influence). cAMP levels drop, leading to a slowing of the heart rate.

Inositol phosphate pathway (Gq proteins)

Another scenario is mediated through Gq proteins, which activate the enzyme phospholipase C. This pathway operates, for example, during the stimulation of vascular smooth muscle α1-adrenergic receptors.

Biochemical cascade:

1. Phospholipase C hydrolyzes membrane phosphatidylinositol 4,5-bisphosphate.
2. The hydrophilic secondary messenger inositol 1,4,5-trisphosphate (IP3) is synthesized.
3. IP3 opens calcium channels of the sarcoplasmic reticulum.
4. Ca²⁺ ions flood into the cytoplasm and form a complex with the protein calmodulin.
5. The "Ca²⁺-calmodulin" complex activates myosin light-chain kinase.
6. Myosin is phosphorylated, facilitating its contact with actin, resulting in vascular contraction.

Amplification phenomenon

A key property of G protein-coupled receptors is the multiple-fold amplification, or amplification, of the primary signal. A single activated receptor can trigger multiple G proteins, and each of these causes enzymes to synthesize hundreds of secondary messenger molecules.

This is the most widespread class of receptors in the body. They include dopamine, histamine, opioid, and certain serotonin receptors, as well as sensors for most peptide hormones.

Class and exam questions

What else to study on this topic

• The mechanism of cellular protein phosphorylation by cAMP-dependent protein kinases.
• The role of the "Ca²⁺-calmodulin" complex in smooth muscle physiology.
• Pharmacological effects of α1- and β1-adrenergic receptor blockers.
• Diversity and functions of opioid receptors.

Other topics in "General Pharmacology"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.