By Luke Sumpter


At Royal Queen Seeds, we’ve taken you through the ins and outs of the endocannabinoid system (ECS). Now, we’re about to dive a little deeper. Join us as we explore new structures that are currently vying for the title of the third cannabinoid receptor—CB3. The ECS governs all manner of processes in the human body, so a potential new addition to this all-encompassing network is a pretty big deal!

The cannabis plant contains hundreds of interesting molecules that, when ingested, create unique biochemical changes in the body. Specifically, numerous members from the cannabinoid and terpene classes bind to receptors of the ECS. As this system mediates many facets of human physiology, ongoing studies are exploring if and how these ECS ligands (chemicals that bind to specific receptors) might work to treat certain conditions.

Additionally, researchers are continuing to study the ECS for additional components hitherto unknown or unclassified. Such findings include the identification of new binding sites for cannabis constituents that might play important roles in the future of medical cannabis.

Below, find out more about the ECS, and meet the main candidates for "CB3", including the intriguing but underrepresented GPR55. As cannabis science continues to move forward at a rapid pace, it pays dividends to keep up to date on these important findings.

A Primer on the Endocannabinoid System

To better understand why the idea of CB3 holds such importance, and how GPR55 is a worthy candidate, we must first cover some of the foundations of the ECS.

The ECS plays a host of vital roles in human physiology. Ultimately, it helps to regulate almost every other system in the body by encouraging a state of balance, otherwise known as homeostasis. But how exactly does it achieve this?

It comes down to a complex dance between different components; namely, receptors, signalling molecules, and enzymes.

  • Cannabinoid Receptors

The “classical” ECS encompasses two types of cannabinoid receptors: cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2). These receptor types are found in many regions of the body, from neurons and immune cells to skin and bone cells. Positioned on the surface of the plasma membrane of cells, these receptors await activation from ECS signalling molecules.

Both CB1 and CB2 belong to a group of receptors called G protein-coupled receptors (GPCRs). When a molecule binds to them, they cause changes to a “G protein” situated on the other side of the plasma membrane. This shift starts a biochemical cascade that catayses the necessary changes within the cell.

The Endogenous Cannabinoids

  • Signalling Molecules — Endocannabinoids

The signalling molecules of the ECS are referred to as endocannabinoids; “endo” meaning “within”. Cells manufacture these chemicals on demand and release them to bind to the cannabinoid receptors of other cells. For example, post-synaptic neurons make endocannabinoids and send them backwards (retrograde) across the synaptic cleft to control incoming neurotransmitter traffic.

There are two endocannabinoids that belong to the classical ECS: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Upon binding to CB1 and CB2 receptors on the surface of cells, these molecules cause internal changes that help to bring our systems back into balance.

Interestingly, endocannabinoids share a similar structure and function to cannabinoids found in the cannabis plant (phytocannabinoids). As such, molecules such as THC are able to bind to our cannabinoid receptors and facilitate cellular changes. Given some researchers view the ECS as a “therapeutic target”, cannabinoids have been subject to increased study for their potential to modulate this vital physiological system.

  • Enzymes

Finally, the third group of components that make up the ECS are enzymes. These proteins manufacture endocannabinoids from other molecules when the body needs them; a process known as synthesis. They also quickly break them down when they have served their purpose; a process known as degradation.

  • Understanding the Endocannabinoidome

Recent discoveries have led researchers to identify additional components of the ECS. Known as the “expanded endocannabinoid system” or “endocannabinoidome”, it includes an array of ligands, 20 metabolic enzymes, and over 20 receptors[1]. This massive addition to the network includes components involved in a host of processes, from pain signalling to gene expression and fat burning. These findings open up the doorway to the many other mechanisms by which cannabinoids might act in the body.

GPR55: The Third Cannabinoid Receptor?

We know that CB1 and CB2 belong to the G protein-coupled receptor class, but cannabinoids bind to other members of this large family as well, including G protein-coupled receptor 55, remembered more simply as “GPR55”. Researchers formerly referred to this site as an “orphan receptor”, as its endogenous ligands remained unknown. However, various ECS ligands are now known to bind to the site, including anandamide[2].

Researchers first isolated and cloned[3] GPR55 in 1999. It appears the receptor shows up in many places within the body. In the central nervous system, high levels of expression are found in the hippocampus (a region of the brain involved in memory and learning) and cerebellum. The receptor also exists in peripheral sites, including cells in the spleen, GI tract, and adrenal glands. Studies have also found high levels of GPR55 expression on certain cancer cells. 

Interestingly, GPR55 has a “low homology”—a different genetic structure—to CB1 and CB2. It shares only 13.5% of the same amino acids (the building blocks of proteins) with CB1, and 14.4% with CB2. Despite this genetic difference, some researchers have landed on the conclusion that GPR55 deserves the title of CB3.

Certain studies use a "knock-out mouse" model to determine the effects of cannabinoids. Essentially, without the genetics that code for these proteins, the mice simply don’t possess CB1 and CB2 receptors. However, given that cannabinoids sometimes still produce effects in these mice, it leads researchers to hunt down other receptor sites where any changes occur.

A study published in the British Journal of Pharmacology tested a range of plant-derived and synthetic cannabinoids[4] on GPR55. The findings indicate that anandamide, 2-AG, CBD, and other molecules successfully bind to GPR55.

Is GPR55 the Third Cannabinoid Receptor?

GPR55 and CBD

But what does this mean for cannabis users? How will these findings change the way we utilise cannabis? Discovering how cannabinoids work in the body helps researchers understand their potential applications in medicine. For example, ongoing studies are exploring the role of GPR55 when it comes to CBD and epilepsy.

The FDA has approved the CBD-containing drug Epidiolex for severe forms of epilepsy. In fact, CBD first entered the spotlight thanks to famous anecdotes regarding children suffering from epileptic seizures.

But just because CBD binds to GPR55 doesn’t mean that it “activates” the receptor. In fact, it plays the role of an antagonist, meaning it inhibits the action of other molecules that activate the site. The effectiveness of CBD may stem from its ability to temporarily block chemicals that increase the excitability of neurons from binding to the GPR55 receptor[5].

Researchers from the University of Lodz in Poland have also suggested that GPR55 receptors could serve as a therapeutic target[6] for irritable bowel disease (IBD), a condition associated with symptoms of fatigue, weight loss, persistent diarrhoea, and abdominal pain. Studies are continuing to determine if blocking the receptor, through the use of antagonists, could help to manage the symptoms of the condition—making CBD a potential candidate.

Additional G Protein-Coupled Receptors

Other members of the G protein-coupled receptor family are included within the broad system of the endocannabinoidome. Let’s take a deeper look at two of them, and see why they might also join the pantheon of cannabinoid receptors in the future.

  • GPR18

The G protein-coupled receptor 18 (GPR18), also known as the N-arachidonoyl glycine (NAGly receptor), is another cannabinoid receptor candidate. Both THC and anandamide bind to GPR18 with high affinity, while CBD only binds with low affinity. This means the receptor shares some characteristics with the CB1 receptor. Because of this, some researchers state that GPR18 should be considered a cannabinoid receptor[7], making it another candidate for the CB3 title.

GPR18 occurs at the highest levels in testicle and spleen tissues, and also shows up in the thymus, small intestine, and white blood cells. Currently, researchers are exploring the role of the receptor in blood pressure control[8] and the regulation of intraocular pressure[9].

  • GPR119

GPR119 is another novel cannabinoid receptor that may play a future role in the management of diabetes. The receptor is primarily expressed in the gastrointestinal tract and beta cells of the pancreas in humans[10]. Currently, only a couple of endocannabinoidome molecules are known to bind to this receptor. Researchers are still exploring which phytocannabinoids modulate GPR119, and its role in regulating weight gain and insulin secretion.

Is GPR55 the Third Cannabinoid Receptor?

The CB3 Receptor: An Evolving Topic

Although researchers discovered the first traces of the ECS in the 1960s, they remain at the very early stages of this journey. They’re currently still mapping it all out, debating the appropriate titles, and finding out exactly how molecules from the cannabis plant impact different receptors. It’s also important to recognise that GPR55 and its related receptors aren’t the only candidates for the CB3 title.

Some scientists claim that TRPV1 (a receptor that detects heat and pain) should receive this honour, as both CBD and anandamide bind to the site[11].

Another group of receptors, known as peroxisome proliferator-activated receptors (PPARs), are also suitable candidates for this position. These sites are located in the nucleus of cells and are involved in gene expression and fat metabolism. An array of cannabinoids interact with these receptors[12], including THC, CBD, THCV, and CBG.

But these sites are just the tip of the iceberg. Future research will likely uncover many other receptors that end up becoming members of an ECS much more extensive than the one we know today. These inevitable changes are simply how science works.

Fields of study are constantly upended by new findings, and what we think we know for certain today may prove shaky tomorrow. At RQS, we’ve made it our mission to stay up to date on this fascinating topic, and you can rely on us to keep you informed about these important changes as they develop.

External Resources:
  1. The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus | SpringerLink https://link.springer.com
  2. The orphan receptor GPR55 is a novel cannabinoid receptor https://www.ncbi.nlm.nih.gov
  3. GPR55 – a putative “type 3” cannabinoid receptor in inflammation https://www.degruyter.com
  4. The orphan receptor GPR55 is a novel cannabinoid receptor https://bpspubs.onlinelibrary.wiley.com
  5. A role of GPR55 in the antiepileptic properties of cannabidiol (CBD) (P2.277) | Neurology https://n.neurology.org
  6. G protein-coupled receptor 55 (GPR55) expresses differently in patients with Crohn's disease and ulcerative colitis - PubMed https://pubmed.ncbi.nlm.nih.gov
  7. So what do we call GPR18 now? https://www.ncbi.nlm.nih.gov
  8. The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure - PubMed https://pubmed.ncbi.nlm.nih.gov
  9. A GPR18-based signalling system regulates IOP in murine eye - PubMed https://pubmed.ncbi.nlm.nih.gov
  10. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity https://www.ncbi.nlm.nih.gov
  11. Endocannabinoid System Components: Overview and Tissue Distribution - PubMed https://pubmed.ncbi.nlm.nih.gov
  12. An update on PPAR activation by cannabinoids https://www.ncbi.nlm.nih.gov
Disclaimer:
This content is for educational purposes only. The information provided is derived from research gathered from external sources.

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Privacy Policy - Royal Queen Seeds

To ensure a safe online environment and guarantee adequate data protection, we strictly comply with all legal requirements. In this privacy statement, we provide information about how and for what purpose data is collected, safety measures, storage periods and contact details.


COMPANY NAME: SNORKEL SPAIN, SL (hereinafter ROYAL QUEEN SEEDS)

C/ Vilar d'Abdelà, 5 (nave 1) CP: 08170 de Montornès del Vallès

+34 937 379 846

support@royalqueenseeds.com


The present Privacy Policy sets out the terms on which we will treat personal data at ROYAL QUEEN SEEDS; this includes any personal data collected through our website https://www.royalqueenseeds.com/ as well as any other data we process in the course of our business activities.

ROYAL QUEEN SEEDS collects the following personal data for the purposes listed below:

SECTION 1 – PERSONAL INFORMATION WE COLLECT

1.1 Account purchases

Account purchases can only be made if you are in possession of a personal account. When you create an account or purchase something from our shop, as part of the buying and selling process we collect the following personal information that you provide to us:

This information is required for delivery. In addition, when you browse our shop, we automatically receive the Internet Protocol (IP) address of your computer. Based on this information, we can optimise your online experience and at the same time protect our online environment.

Purpose of data collection

We collect and store account-related data for the following purposes:

(a) to carry out obligations arising from any contracts between you and us, and to provide you with information, products and services that you may request from us;

(b) to set up, manage and communicate with you about your account and your orders;

(c) to conduct market research and analysis;

(d) to confirm your age and identity, and to detect and prevent fraud.

1.2 Newsletters

With your explicit permission, we may send you newsletters about our shop, new products and other updates. We send newsletters based on your explicit consent. In the event that you purchase a product, and in accordance with current regulations, we may send you commercial communications in accordance with the legitimate interest of our company, always about products or services similar to those you have purchased or contracted. In any case, you may exercise your right of opposition through the channels announced in this Privacy Policy. The following information is collected in relation to the newsletter:

We do not need to know the sex of the person in order to send the newsletter (data minimisation: by law we must ask for data that is strictly necessary to provide the service, and in this case knowing the sex is not necessary to send the newsletter).

Purpose of data collection

The data collected is used to:

(a) personalise our emails, including your name and gender;

(b) provide gender-specific content.

You can withdraw your consent at any time by using the link provided in the newsletter or the contact information provided in section 2.

1.3 Customer service and contact form

In order to provide appropriate support, our customer service employees have access to information related to the account. Consequently, their support will be highly effective and friendly. The data provided in our contact form is used by our CRM provider, SuperOffice. We will only use your details to respond to your message.

SECTION 2 – LEGITIMATE INTEREST

If you have purchased any of our products, please note that we may process your personal data for promotional purposes, based on Royal Queen Seeds' legitimate interest only to offer you products or services from our company and about products or services similar to those you have purchased. You may exercise your right to opt out of future messages by the means set out in this Privacy Policy or through any notification you receive.

2.1 How do you withdraw consent?

If you change your mind, you can withdraw your consent for us to contact you for the purpose of collecting, using, or disclosing your data at any time by reaching out to us at: support@royalqueenseeds.com.

SECTION 3 – DISCLOSURE

We may disclose your personal information if we are required to do so by law or if you breach our Terms of Service.

SECTION 4 – HOW LONG DO WE KEEP YOUR DATA?

At Royal Queen Seeds, we will not retain your data for longer than is necessary for the purposes described in this Policy. Different retention periods apply for different types of data; however, the longest period we will normally hold any personal data is 10 years.

4.1 Account information

Data relating to the account remains relevant for as long as the consumer is in possession of an account. Therefore, the data remains documented for as long as the account exists. When our customers delete an account, the associated data will be deleted within a reasonable period of time. Requests regarding the inspection or correction of stored personal data or the deletion of an account can be sent to support@royalqueenseeds.com.

4.2 Newsletters

In the event that you give us your consent to inform you about our products or services, we will keep your data until you express your wish not to receive any further communications from us. However, we regularly (every month) carry out a relevance check. Registered customers (and their personal information) will be deleted whenever customers do not reply to our request. In addition, our newsletter mailing has an opt-out feature. Consumers can withdraw their consent by using this opt-out feature.

SECTION 5 – COOKIES

Cookies are small information files that notify your computer of previous interactions with our website. These cookies are stored on your hard drive, not on our website. Essentially, when you use our website, your computer displays its cookies to us, informing our site that you have visited before. This allows our website to function more quickly and remember aspects related to your previous visits (such as your username), making your experience more convenient. At Royal Queen Seeds, we use two types of cookies: functional and analytical.

5.1 Functional Cookies

Functional cookies are used to enhance your online experience. Among other things, these cookies track what is added to your shopping cart. The use of these cookies does not require prior authorization.

5.2 Analytical Cookies

Analytical cookies are used for research and market analysis. The data collected with these analytical cookies is anonymous, making it unusable for third parties. The use of these cookies does not require prior authorization.

SECTION 5 – THIRD-PARTY SERVICES

Third-party services are required to conduct transactions and provide our services. In general, the third-party providers we use will only collect, use and disclose your information to the extent necessary to enable them to perform the services they provide to us.

However, certain third-party service providers, such as payment gateways and other payment transaction processors, have their own privacy policies regarding the information we must provide to them for your transactions.

We encourage you to read the privacy policies of these providers so that you can understand how these providers will handle your personal information.

In particular, certain suppliers may be located or have facilities located in a different jurisdiction than yours or ours. Therefore, if you choose to proceed with a transaction involving the services of a third party, your information may be subject to the laws of the jurisdiction in which that service provider or its facilities are located.

Once you leave our website or are redirected to a third-party website or application, you are no longer governed by this Privacy Policy or the Terms of Service of our website.

Web analytics service (anonymous data)

On this website we have integrated an element of a web analytics service (with anonymisation functionality). Web analytics can be defined as the gathering, processing and analysis of data about the behaviour of visitors to websites. An analytics service collects, among other things, data about which website a person came from (the so-called referrer), which sub-pages they visited or how often and for how long they visited a sub-page. Web analytics is mainly used for website optimisation and for a cost–benefit analysis of internet advertising.

Courier service

To complete deliveries we use a courier service. This courier service carries out the delivery between our company and the consumer's home. To complete these logistics, the company requires access to the consumer's name and address information.

Mailing service

Royal Queen Seeds uses a third-party mail service provider to send its newsletter. This provider has access to limited account information related to opt-in consent (e.g. email address).

Marketing services

Royal Queen Seeds has the support of a company that specialises in marketing and communication activities. Their access to personal information is very limited and mostly anonymous.

Payment services

At Royal Queen Seeds we use external payment services to handle our transactions (e.g. credit card payments).

SECTION 6 – SECURITY

To protect your personal information, we take reasonable precautions and follow industry standard best practices to ensure that it is not inappropriately lost, misused, accessed, disclosed, altered or destroyed.

If you provide us with your credit card information, the information is encrypted using secure socket layer technology (SSL) and stored using AES-256 encryption. Although no method of transmission over the internet or electronic storage is 100% secure, we follow all PCI-DSS requirements and implement additional industry standards that are commonly accepted. Information related to the account is protected with a hashing method. This method transforms the information into a generated hash. As a result, confidential information is protected and invisible, even to us. In addition, our databases are exceptionally protected against unauthorised access. For example, access to the database is only possible and permitted via approved IP addresses (e.g. from Royal Queen Seeds headquarters). Other attempts and addresses are rejected at all times.

Furthermore, data is anonymised as much as possible, so it cannot be directly linked to a specific consumer. With this data, however, we may be able to carry out market research and analysis. In addition, the third parties concerned (e.g. mailing service) are examined prior to our collaboration, comply with the GDPR from the EU and receive a processing agreement. Within Royal Queen Seeds, employees are assigned different access permissions. Specific permission provides access only to information that is strictly required to perform a task. Digital security measures are subject to change and must meet high requirements to ensure the safety of online customers. That is why, at Royal Queen Seeds, we appoint a security officer. Regular verification and improvement of security measures (where necessary) are part of the role.

SECTION 7 – CHANGES TO THIS PRIVACY POLICY

We reserve the right to modify this Privacy Policy at any time, so please check back regularly. Changes and clarifications will be effective immediately upon being published on the Website. If we make substantial changes to this policy, we will notify you here that it has been updated so you will know what information we collect, how we use it and under what circumstances, if any, we use and/or disclose it.

SECTION 8 – YOU HAVE THE RIGHT TO: