GPR55: The Orphan Receptor That Might Be the Third Cannabinoid Receptor — Or Might Not

An Orphan Gets a Name

GPR55 was one of thousands of orphan G-protein-coupled receptors — genes encoding receptor proteins whose function and natural ligands were unknown. AstraZeneca's drug discovery division in Mölndal, Sweden, was systematically testing these orphans against panels of known drug molecules to figure out what they respond to. It's a pharmaceutical fishing expedition: transfect cells with the orphan receptor gene, expose them to hundreds of compounds, and see what activates them.

When they tested GPR55 against cannabinoids, the results were striking.

The headline finding: GPR55 responds to the same cannabinoid molecules that activate CB1 and CB2. THC, anandamide, 2-AG — they all bind and activate this orphan receptor. If it looks like a cannabinoid receptor and it responds like a cannabinoid receptor...

The paper's title made the claim directly: "The orphan receptor GPR55 is a novel cannabinoid receptor."

The field immediately pushed back.

The Case for CB3

The same year Ryberg published this paper, Shingo Oka's group in Japan demonstrated that GPR55's endogenous ligand is lysophosphatidylinositol (LPI) — a lipid that is not an endocannabinoid. If the receptor's natural activator isn't a cannabinoid, can the receptor truly be called a cannabinoid receptor?

Roger Pertwee wrote an accompanying editorial in the same journal issue titled "GPR55: a new member of the cannabinoid receptor clan?" — the question mark in the title telling you everything about the field's uncertainty.

How Different Is GPR55, Really?

The comparison makes the problem clear. CB1 and CB2 share 44% of their sequence, use the same G-protein family (Gi/o), respond to the same endocannabinoids, and inhibit the same enzyme (adenylate cyclase). They're recognizably related — siblings with different jobs.

GPR55 shares only 13-14% sequence identity with either. It uses a completely different G-protein (Gα13). Its natural ligand isn't a cannabinoid. Its downstream signaling (cytoskeletal regulation via rhoA) has nothing in common with classical cannabinoid signaling (adenylate cyclase inhibition). It responds to cannabinoids, but it's built differently, signals differently, and evolved for something different.

Is a receptor that responds to cannabinoids automatically a cannabinoid receptor? Or is "cannabinoid receptor" a functional family defined by more than just ligand overlap?

The field hasn't agreed.

What GPR55 Actually Does

Regardless of whether it's called CB3, GPR55 has real biology that matters:

The bone finding is particularly intriguing. GPR55 promotes osteoclast function — the cells that break down bone. Without GPR55, mice have denser, stronger bones. This suggests GPR55 antagonists could treat osteoporosis — a therapeutic angle completely unrelated to cannabis but enabled by this receptor's cannabinoid responsiveness.

The cancer connection is equally compelling. GPR55 is overexpressed in multiple cancer types — acute myeloid leukemia, uveal melanoma, glioma, renal cancer. Tumor cells appear to co-opt GPR55 signaling to increase motility and aggressiveness. Blocking GPR55 reduces cancer cell migration.

Which brings us to CBD.

Why CBD Blocks GPR55 — and Why That Matters

One of the paper's most practically important findings was that CBD is a potent GPR55 antagonist — it blocks the receptor at nanomolar concentrations (IC50 = 445 nM) without activating it.

This has direct implications for understanding CBD's therapeutic profile:

This doesn't prove CBD cures cancer — the evidence is preclinical and far from clinical application. But it does provide a mechanistic pathway through which CBD's anti-cancer effects in laboratory models might work, independently of cannabinoid receptors CB1 and CB2.

The Bigger Question: How Many Receptors Are There?

Myth vs. Reality

✕Myth

The endocannabinoid system has two receptors — CB1 and CB2. That's it.

✓Reality

Multiple other receptors respond to cannabinoids. GPR55, GPR18, and GPR119 are all G-protein-coupled receptors activated by various cannabinoids. TRPV1 (a vanilloid receptor) is activated by anandamide and CBD. PPARα and PPARγ (nuclear receptors) respond to both endocannabinoids and phytocannabinoids. The 'two receptors, two endocannabinoids' model is a useful simplification, not the full picture.

The Evidence

Ryberg et al. (2007) demonstrated GPR55 responds to THC and endocannabinoids. Anandamide was shown to activate TRPV1 by Zygmunt et al. (1999). CBD activates 5-HT1A serotonin receptors. The endocannabinoid system's boundaries are blurrier than textbooks suggest — it overlaps with the endovanilloid system, serotonin signaling, and lipid signaling networks that extend far beyond two receptors.

Ryberg et al. (2007); Zygmunt et al. (1999); Pertwee (2008)

GPR55's story is really about the limits of tidy categories. The endocannabinoid system was discovered through cannabis — we found the receptors by looking for what THC binds. But the body's lipid signaling networks don't respect the boundaries we drew around "the cannabinoid system." GPR55 may be part of it, or it may be part of a different but overlapping system. The molecules don't care what we call the receptor families. They bind what they bind.

This is why cannabinoid pharmacology is more complex than most popular descriptions suggest — and why cannabis produces such a wide range of effects. The plant's molecules interact with a network of receptors that extends beyond the two we've named "cannabinoid."

Frequently Asked Questions

Is GPR55 the third cannabinoid receptor (CB3)?

It's genuinely unclear — and that's what makes this study important. GPR55 is activated by THC, anandamide, 2-AG, and other cannabinoids, which makes it look like a cannabinoid receptor. But it shares only 13-14% of its amino acid sequence with CB1 or CB2, uses completely different intracellular signaling (Gα13 instead of Gi/o), and its primary natural ligand is a non-cannabinoid lipid called lysophosphatidylinositol (LPI). The International Union of Pharmacology (IUPHAR) has not officially designated it as CB3. Most researchers describe it as a "putative" or "atypical" cannabinoid receptor. The biology matters more than the label.

Why does it matter whether GPR55 is a cannabinoid receptor or not?

Because it affects how we understand both the scope of the endocannabinoid system and how CBD works. CBD is a potent GPR55 antagonist (blocker), and GPR55 is overexpressed in several cancer types where it promotes tumor cell migration. CBD's anti-cancer effects in laboratory models may partly work through GPR55 blockade — a mechanism completely independent of CB1 or CB2. Whether we call it "CB3" or not, GPR55 clearly responds to cannabinoids and has real physiological relevance for bone density, pain, and cancer.