G Protein-Coupled Receptors and Their Role as Drug Targets

G protein-coupled receptors (GPCRs) are expressed on the surface of cells and regulate a range of important functions. Because they are involved in so many sensory and physiological processes, including diseases such as cancer, they are the targets of a large number of currently available drugs. In this article, discover how GPCRs govern the body’s senses, their role in disease processes, and why they are such attractive therapeutic targets.

The three-dimensional structure of a GPCR protein, with pink and blue shaded alpha helices — Expressed on the surface of cells, GPCRs are responsible for a wide range of functions in humans, from smell to endocrine signaling.
iStock, Miyako Nakamura

What Are GPCRs?

GPCRs are a large family of transmembrane receptors that bind a wide variety of extracellular ligands.¹ They are the largest class of membrane proteins in humans and are responsible for almost every type of physiological function, from sensing the external environment to maintaining internal homeostasis.²

GPCRs have an intracellular carboxyl (C) terminus and an extracellular amino (N) terminus, and seven transmembrane (7TM) domains, meaning that the protein passes through the cell membrane seven times.¹ The transmembrane-spanning α helices of the protein are separated by alternating extracellular and intracellular loops.

The three hydrophilic extracellular loops are often glycosylated and contain conserved disulfide bonds that help stabilize the receptor.¹ These extracellular loops form a ligand-binding pocket on the surface of the cell, while the three intracellular loops are involved in signal transduction.³

GPCR Signaling

How do GPCRs work?

As their name suggests, GPCRs are coupled to G proteins (guanine-nucleotide-binding regulatory proteins), which are linked to the intracellular C-terminus of the GPCR.⁴ When a GPCR binds to its ligand and becomes activated, it uses these G proteins to trigger intracellular signaling cascades, which result in a physiological response.⁴

How do GPCRs activate G proteins?

G proteins are heterotrimers, made up of α, β, and γ subunits.⁴ When a GPCR binds to its ligand, it undergoes a conformational change, acting as a guanine nucleotide exchange factor and activating the α subunit of its associated G protein.⁴ The Gα subunit releases inactive guanosine diphosphate (GDP) and exchanges it for active guanosine triphosphate (GTP), then it disassociates from the Gβγ subunit, allowing both to act as secondary messengers.⁵ Downstream signal transduction occurs through either the cyclic AMP (cAMP) or phosphatidylinositol pathway.

Illustrated infographic depicting GPCR activation at the plasma membrane via signal molecule binding to the receptor’s external surface. Internally, the G-protein alpha subunit associated with the activated GPCR exchanges GDP for GTP and separates from the beta and gamma subunits, allowing the alpha and beta/gamma subunits to act as secondary messengers in known and unknown signaling pathways. — GPCRs are transmembrane receptors that bind different extracellular ligands to activate G proteins inside the cell, which have many known and unknown roles, including regulating olfaction, taste, vision, cognition, movement, hormone signaling, immune function, and metabolic signaling.
Modified from ©istock.com, VectorMine; Designed by Greg Brewer

GPCR Classes

Scientists who study GPCRs still debate how to classify them. Many researchers believe GPCRs should be classified based on a combination of their structural and functional features—for example, how they bind to ligands.⁵

In contrast, the GRAFS system classifies GPCRs based on their placement in a phylogenetic tree. In the latter system, they are grouped into five families.⁶

Glutamate (G)
Rhodopsin (R)
Adhesion (A)
Frizzled/Taste2 (F)
Secretin (S)

The rhodopsin-like family is the largest and most diverse, containing 85 percent of known human GPCRs.⁷

GPCR Functions

Humans have a repertoire of more than 800 GPCRs, which bind a range of ligands including metabolic products, fatty acids, hormones, and neurotransmitters.¹ Around half of human GPCRs are responsible for olfaction and are known as olfactory receptors (ORs).⁸ ORs belong to the rhodopsin family and are typically expressed in the olfactory sensory neurons that line the olfactory epithelium of the nasal cavity, where they bind to volatile odors to facilitate our sense of smell.⁸

Many GPCRs, such as metabotropic glutamate receptors (mGluRs), are highly expressed in the brain and spinal cord, where they bind neurotransmitters to regulate movement and cognition.⁹ Others play key roles in the endocrine system. For example, the G protein-coupled estrogen receptor 1 (GPER1) binds to estrogen in various tissues and is thereby involved in growth, reproduction, and cardiovascular health, among other functions.¹⁰

GPCRs also regulate immune function, metabolism, and other senses, such as gustation (taste) and vision. However, many human GPCRs have unknown functions; scientists are still elucidating the ligand-binding capability and function of these so-called “orphan” GPCRs.⁸

GPCRs as Therapeutic Targets

GPCR dysregulation and mutations in their encoding DNA sequences can contribute to many diseases, including neurological, cardiac, metabolic, endocrine, immune, ophthalmological, and pulmonary diseases.⁸ Because these proteins are crucial for so many aspects of human physiology, a range of drugs exploit GPCRs as therapeutic targets. In fact, 34 percent of current medications are drugs targeting GPCRs, and many more GPCR-targeted drugs are currently in development.²

Dysregulated GPCRs can also be involved in cancer. GPCRs are well-established drivers of tumor growth, angiogenesis, and metastasis. For example, the overexpression of certain GPCRs, such as the protease-activated receptor (PAR1), is associated with the proliferation of many cancer cell types.¹¹ As such, scientists are currently exploring PAR1 inhibitors as therapeutic interventions in some cancers, including breast cancer.¹² Mutations in GPCRs or their associated G proteins can also underpin the growth of endocrine tumors.¹¹

Mutations in the gene sequence of specific GPCRs can strongly affect how people respond to certain drugs. Variations in the HTR2A gene, which encodes the serotonin 2A receptor, can reduce its expression levels and thereby affect the response to serotonin reuptake inhibitors, which are commonly prescribed to treat depression.¹³ Additionally, mutations in the µ opioid receptor are sometimes associated with addiction to opioid medications, while other mutations in the same gene appear to have a modest protective effect against substance dependence.¹⁴

Another GPCR, the β1 adrenergic receptor encoded by the ADRB1 gene, is the target of β-blocker drugs for the treatment of hypertension. Patients carrying common ADRB1 mutations that alter the function of the receptor demonstrate enhanced responses to commonly prescribed beta blockers, such as metoprolol.¹⁵

Researchers continue to study GPCRs, discovering more of their functions and revealing how they are involved in disease pathogenesis. As scientists learn more about this critical group of receptors, more GPCR-targeted drugs can potentially be developed for the treatment of cancer and other diseases.

References