Physiological Functions of GPCRs
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- Recombinant Proteins
- Native Proteins
- GMP Proteins
- Fluorescent Dyes
- Physiological Functions of GPCRs Information
- GPCRs Class A
- GPCRs Class B
- GPCRs Class C
- GPCRs Class F
- GPCRs Taste/Vomeronasal Receptors
- Physiological Functions of GPCRs
- How Do GPCRs Work?
- Dysregulation of GPCRs
- GPCRs Desensitization
- GPCRs Diseases
- G-protein coupled receptor (GPCR) pathways
- GPCRs Subfamily
- G-protein Signaling
Ligands/receptors proteins
Interacting Proteins
Inhibitors/promotors
Substrate
Class A rhodopsin-like
Class B secretin-like
Metabotropic glutamate/pheromone
Class F frizzled (FZD)
Other GPCRs
GPCRs play diverse and vital physiological roles in many fundamental biological processes. These receptors are also important regulators of physiology in all systems—the nervous, endocrine, cardiovascular, immune and sensory. In transducing signals from various extracellular triggers, including hormones, neurotransmitters and environmental stimuli, GPCRs control cellular response to homeostasis and respond to changes in the internal and external environment.
Fig. 1: Examples of the physiological roles of GPCRs. GPCRs, G protein-coupled receptors; GABA, gamma-Aminobutyric acid; NPY, neuropeptide Y (DeMorrow and Leyva-Illades, 2013).
Nervous System
GPCRs play a wide role in neurotransmission and neuroregulation, which is why they play such an important role in the central and peripheral nervous systems. They regulate synaptic transmission, modulate neuronal excitability and control neuroplasticity—with consequences for learning, memory and mood.
Neurotransmitter Signaling
GPCRs serve as receptors for several neurotransmitters, including serotonin, dopamine, norepinephrine, and acetylcholine. These receptors help modulate mood, cognition, reward, and motor control.
- Serotonin Receptors (5-HT receptors): These GPCRs regulate mood, anxiety, and sleep patterns. Dysregulation of serotonin signaling is associated with psychiatric disorders such as depression and anxiety.
- Dopamine Receptors (D1-D5 receptors): Dopamine GPCRs play roles in motor function, motivation, reward, and addiction pathways. Dopaminergic signaling is crucial in diseases like Parkinson’s disease and schizophrenia.
Autonomic Nervous System Regulation
GPCRs are responsible for mediating the effects of the sympathetic and parasympathetic nervous systems. For example:
- Adrenergic Receptors: These GPCRs respond to catecholamines such as epinephrine and norepinephrine and regulate heart rate, blood pressure, and smooth muscle contraction.
Endocrine System
In the endocrine system, GPCRs mediate the actions of hormones, influencing metabolism, growth, and reproductive functions. They are involved in the regulation of hormone release and action in tissues.
Hormonal Regulation
GPCRs control the secretion of hormones and their subsequent signaling pathways in target cells. Some key examples include:
- Thyroid-stimulating Hormone Receptor (TSHR): This GPCR regulates thyroid function by controlling the release of thyroid hormones, which influence metabolism, growth, and development.
- Glucagon Receptor: It regulates glucose metabolism by stimulating gluconeogenesis and glycogenolysis in the liver, thereby increasing blood glucose levels during fasting.
Reproductive Function
- Gonadotropin-releasing hormone receptor (GnRHR): GnRHRs regulate reproductive hormone secretion, playing roles in fertility, sexual development, and the menstrual cycle.
- Oxytocin receptor (OTR): This GPCR mediates uterine contractions during childbirth and is involved in social bonding and maternal behaviors.
Cardiovascular System
GPCRs are central regulators of cardiovascular function, controlling heart rate, blood pressure, and vascular tone. By responding to hormones, neurotransmitters, and local factors, they ensure proper blood flow and pressure regulation.
- Adrenergic Receptors (β1, β2, α1, α2 receptors): These GPCRs respond to catecholamines and are responsible for modulating heart rate, force of contraction, and blood vessel dilation or constriction. β1-Adrenergic receptors in the heart increase heart rate and force of contraction, whereas β2-adrenergic receptors mediate smooth muscle relaxation in blood vessels. α1-Adrenergic receptors promote vasoconstriction, thereby increasing blood pressure.
- Angiotensin II Receptor (AT1R): This GPCR is part of the renin-angiotensin system and regulates blood pressure by inducing vasoconstriction and promoting sodium and water retention. Overactivity of this receptor contributes to hypertension and cardiovascular disease.
Immune System
GPCRs are important in regulating the immune system by controlling the activity of immune cells such as lymphocytes, macrophages, and neutrophils. They modulate immune responses, inflammation, and cell trafficking during immune surveillance and responses to infections or injuries.
- Chemokine Receptors: These GPCRs direct the movement of immune cells to sites of infection or injury. They control leukocyte migration (chemotaxis) during immune responses and inflammation.
- Histamine Receptors (H1-H4): These GPCRs mediate allergic and inflammatory responses by regulating immune cell activation, vasodilation, and vascular permeability.
- Purinergic Receptors (P2Y Receptors): These GPCRs regulate immune cell activation, cytokine release, and inflammation. They respond to extracellular nucleotides such as ATP released during cell damage.
Sensory Systems
GPCRs are integral to the sensory perception of light, taste, smell, and pheromones, enabling organisms to detect and respond to environmental stimuli.
Vision
The GPCR rhodopsin is responsible for light detection in the retina. It plays a crucial role in the phototransduction cascade, which converts light signals into electrical signals processed by the brain. Rhodopsin in rod cells allows for vision in low-light conditions, while related GPCRs in cone cells detect different wavelengths of light for color vision.
Olfaction (Smell)
Olfactory receptors (ORs) are a large family of GPCRs responsible for detecting odorants. Each receptor responds to specific chemical structures, allowing the brain to identify and differentiate between thousands of different smells. Humans have around 400 functional olfactory receptors, each recognizing different molecular features of odorants.
Taste
GPCRs are also involved in detecting sweet, bitter, and umami tastes. The TAS1R and TAS2R families of taste receptors are responsible for identifying these specific taste modalities.
Metabolism and Energy Homeostasis
GPCRs regulate metabolic processes by influencing energy balance, appetite, and glucose metabolism. They play key roles in maintaining metabolic homeostasis and responding to nutritional changes.
- Glucagon-like Peptide-1 Receptor (GLP-1R): This GPCR is involved in glucose metabolism by stimulating insulin secretion in response to food intake, thereby regulating blood glucose levels. It is a therapeutic target for managing type 2 diabetes.
- Free Fatty Acid Receptors (FFARs): These GPCRs respond to circulating fatty acids and regulate insulin secretion, energy expenditure, and inflammation. They play roles in metabolic diseases, including diabetes and obesity.
Cell Growth and Development
GPCRs influence cell proliferation, differentiation, and migration, processes that are critical during embryonic development, wound healing, and tissue regeneration.
- Frizzled Receptors (FZD): These GPCRs are key components of the Wnt signaling pathway, which is involved in embryonic development, stem cell regulation, and tissue regeneration. Abnormal Wnt signaling via Frizzled receptors can lead to developmental disorders and cancers.
- Smoothened Receptor (SMO): This GPCR is part of the Hedgehog signaling pathway, which regulates tissue patterning and cell differentiation during development. Mutations in SMO are implicated in cancers such as basal cell carcinoma.
Pain Perception
GPCRs mediate the sensation of pain through their action on sensory neurons and their regulation of inflammatory mediators.
- Opioid Receptors (μ, κ, δ): These GPCRs are targets for endogenous opioids (e.g., endorphins) and opioid drugs (e.g., morphine), mediating pain relief by inhibiting pain transmission in the central nervous system. They are crucial for managing pain but are also involved in the development of tolerance and addiction.
- Cannabinoid Receptors (CB1, CB2): These receptors modulate pain perception, inflammation, and immune function. CB1 receptors are found predominantly in the brain and mediate the psychoactive effects of cannabinoids, while CB2 receptors are primarily located in immune cells and are involved in anti-inflammatory responses.
Reproductive System
GPCRs regulate various reproductive processes, including gametogenesis, hormone release, and sexual development.
- Follicle-Stimulating Hormone Receptor (FSHR): This receptor regulates ovarian follicle maturation in females and spermatogenesis in males. It is crucial for fertility and reproductive health.
- Luteinizing Hormone Receptor (LHR): LHR is involved in the regulation of ovulation and the maintenance of the corpus luteum in females, as well as testosterone production in males.
Reference
- DeMorrow, S. & Leyva-Illades. (2013). Orphan G protein receptor GPR55 as an emerging target in cancer therapy and management. Cancer Management and Research , 147.