G Protein-Coupled Receptors (GPCR)

Overview

• G protein-coupled receptors (GPCR) 
  • 7 transmembrane domain receptors on the cell membrane that sense the external environments
  • ligands activate the G protein by causing a conformational change
  • this change propagates to a second messenger which detaches from the GPCR to carry the signal to other effector proteins
• 3 types of GPCR second messengers and functions
  • G_q activates phospholipase which results in the formation of
    • inositol phosphate (IP₃) → ↑ [Ca²⁺] 
    • diacylglycerol → activation of protein kinase C (PKC)
    • examples of receptor types: α₁, H₁, V₁, M₁, M₃
  • G_s activates adenyl cyclase resulting in  
    • ↑ cAMP → ↑ activity of protein kinase A (PKA) 
    • examples of receptor types: β₁, β₂ , D₁, H_2, V₂ 
  • G_i inhibits adenyl cyclase resulting in 
    • ↓ cAMP → ↓ activity of protein kinase A (PKA)
    • examples of receptor types: α₂, D₂, M₂ 

Receptor	GPCR Class	Locations and Major Functions
Adrenoceptor: Sympathetic System
α1	q	GI and GU: contraction of sphinctersEye: contraction of iris radial muscle (mydriasis) Vasculature: vasoconstriction
α2	i	GI: ↓ motilityVasculature: vasoconstriction of veins and arteries in heart BUT vasodilation of arteriesPresynaptic adrenergic nerve terminals: ↓ sympathetic outflow by inhibiting NE releaseLipocytes: ↓ decreases lipolysisPancreas: ↓ insulin and ↑ glucagonPlatelets: stimulation of platelet aggregation
β1	s	Heart: positive chronotrope and inotropeKidney: ↑ renin releaseLipocytes: ↑ lipolysis
β2	s	Vasculature: vasodilation (specifically skeletal muscle vasculature)Lung: bronchodilationGI and GU: bladder and uterus relaxation Heart: positive inotrope and chronotropeEye: ciliary muscle relaxationLipocytes: ↑ lipolysisPancreas: ↑ insulin releaseLiver: ↑ gluconeogenesis and glycogenolysis
Cholinoreceptors: Parasympathetic System
M1	q	CNS: excitatory in the CNSGlands: ↑ salivary, sweat, and stomach secretions
M2	i	Heart: negative chronotrope and ↓ contractility of atria
M3	q	Glands: ↑ salivary, sweat, stomach glandsGI and GU: ↑ motility, ↑ bladder and uterus contractionLung: bronchoconstrictionEye: ciliary and iris circular muscle contraction
Dopaminergic Receptors
D1	s	Kidney: renal vascular smooth muscle relaxation
D2	i	Brain: modulates neurotransmitter release
Other G Protein-Coupled Receptors (Histamine and Vasopressin)
H1	q	Glands; ↑ nasal and bronchial mucus secretionLung: bronchoconstrictionSkin: pruritus (itching), ↑ pain and irritation
H2	s	GI: ↑ gastric acid secretion
V1	q	Vasculature: vasoconstriction
V2	s	Kidney: antidiuretic, ↑ water permeability and reabsorption in the collecting tubules

G Protein-Coupled Receptors (GPCRs) are a large family of cell membrane proteins that play a critical role in cellular signaling. They are involved in a wide range of physiological processes and are the target of many drugs.

Structure of G Protein-Coupled Receptors

GPCRs are composed of a single polypeptide chain that spans the cell membrane seven times, forming seven alpha-helical transmembrane domains (TM). The N-terminus of the receptor is located on the extracellular side of the membrane, while the C-terminus is located on the intracellular side. The extracellular loops and the N-terminus are involved in ligand binding, while the intracellular loops and the C-terminus interact with intracellular signaling proteins.

Ligand Binding and Activation

GPCRs can be activated by a variety of ligands, including hormones, neurotransmitters, and other signaling molecules. When a ligand binds to the receptor at the extracellular surface, it induces a conformational change in the receptor, which leads to the activation of the G protein.

G Proteins

G proteins are a family of proteins that act as molecular switches in signaling pathways. They consist of three subunits: alpha (α), beta (β), and gamma (γ). In an inactive state, the α-subunit is bound to GDP (guanosine diphosphate). Upon activation of the GPCR, the α-subunit exchanges GDP for GTP (guanosine triphosphate) and dissociates from the βγ-subunits. Both the α-subunit and the βγ-subunits can then interact with various effector proteins to initiate downstream signaling cascades.

Signal Transduction

The activated G protein α-subunit or the βγ-subunits can modulate the activity of various intracellular effector proteins, such as enzymes or ion channels. This leads to the generation of intracellular second messengers, such as cyclic AMP (cAMP), calcium ions (Ca2+), or inositol trisphosphate (IP3), which further transmit the signal and trigger specific cellular responses. GPCRs can activate multiple signaling pathways simultaneously, allowing for complex and diverse cellular responses.

Regulation (G Protein-Coupled Receptors)

GPCR signaling is tightly regulated to maintain cellular homeostasis. The desensitization and internalization of GPCRs can occur through mechanisms such as receptor phosphorylation by kinases, followed by the binding of arrestin proteins, which prevent further signaling. GPCRs can also be regulated by other proteins, such as G protein-coupled receptor kinases (GRKs) and regulators of G protein signaling (RGS proteins), which modulate the duration and intensity of signaling.

Importance of G Protein-Coupled Receptors

GPCRs are the largest class of membrane receptors and are involved in numerous physiological processes, including sensory perception, neurotransmission, hormone regulation, immune responses, and cardiovascular function. Due to their essential role in cellular signaling, GPCRs are a major target for pharmaceutical intervention, with a significant number of drugs on the market designed to modulate GPCR activity.

In summary, GPCRs are cell membrane proteins that transmit signals from extracellular ligands to intracellular signaling pathways, playing a critical role in many physiological processes. Their diverse functions and pharmacological importance make them a subject of extensive research in biology and medicine.

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