Μ Opioid Receptors

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Revision as of 22:05, 22 April 2015

The µ opioid receptor (MOR) is the mediator of opioid interactions with the body. It is a well characterized and prevalent protein. Opium is one of the oldest drugs in use in the world, with derivatives like morphine, heroin, and codeine which are among the most widely used recreational and clinical drugs. Opioid compounds are found throughout nature in plants and in endogenously produced horomones. Opioid receptors are mitigation points of pain within the body, that is why codeine and morphine are used as pain relievers because they are agonistic to the MOR. This makes the subject of the µ opioid receptor a topic of considerable conversation ^[1] The structure of the MOR is one that includes it in a large superfamily of globular protein coupled receptors (GPCR) which have seven transmembrane-spanning helices ^[2]. The location of these helices can be found on the plasma membranes of dendritic cells, the sarcolemma which composes the outer portion of muscle of a muscle cell, at points of focal adhesion, and more ^[3]. Presently there are 10 known variants within the human body of the MOR, however given their prevalence in cells there may be more yet to be discovered ^[4].

Function:

There is still much to learn about MOR, their activation by opioids, and the connection to other proteins. There has been a traditional explanation of the MOR based on its interactions with GABA (gamma aminobutyrate) ^[5]. GABA is an inhibitory neurotransmitter in adult mammalian brains and is a multifunctional molecule with situational functions acting mainly in the central nervous system. Depending on the situation GABA acts as an excitatory or deactivating signal to neurons ^[6]. It has been established that the MOR when activated by opioids regulates the excitability (mediating pain) of neurons through interactions with GABA in such a way that it suppresses the release of GABA from inhibitory neurons through the changing on Cl- ion channeling and concentration. However, further research into the MOR has revealed action which challenges this classical function. Through activation of the MOR in synapses, opioids have been shown to actually collapse preexisting dendritic spines and receptors ^[7].

Structure:

Through research methods and crystallography specifics of the MOR have been identified. Helices run parallel to each other through the membrane in a pattern of alternating aqueous and lipid layers. Receptors are arranged in parallel dimers that are associated with the helices, specifically helices 5 and 6. The seven transmembrane spanning alpha helices of the MOR are connected to each other through extracellular and intracellular loops. There are various types of stabilizing bonds that are utilized by the MOR to maintain its structure within the membrane. Some of these bonds include disulfide bridges between transmembrane helices to cellular loops and covalent bonding between ligand and side chains of the helices. Individual MORs associate through receptor monomers that are pairwise along the sides of two interfaces. The first interface is between transmembrane helices, the second and stronger of the two occurs between transmembrane helices 5 and 6. These associations suggest that the MOR works as a dimer or higher order oligomer ^[8]. The ligand binding pocket of the MOR is unique amongst the GPCR family. In many GPCRs the ligand pocket is partially buried by side chains of the transmembrane helices. MOR on the other hand has it's binding pocket mostly exposed to the extracellular surface. This is an important distinction because it creates a huge difference in the kinetics of ligand binding and competition with agonists. For example, muscarinic receptor ligands are covered by a layer of tyrosines and correspondingly have very slow kinetics of dissociation. Some clinical drugs that act upon this receptor having half lives of 34 hours. Comparatively, potent opioids (ex. Buprenorphine) have a rapid dissociation half life of 30-40 minutes. It is because of this exposed ligand pocket that an agonist (ex. naloxone) could act so quickly on someone who is overdosing on heroin ^[9].

Research:

References:

1. ↑ Pan L., Xu J., Yu R., Xu M., Pan Y -X., Pasternak G.W. Identification and characterization of six new alternatively spliced variants of the human μ opioid receptor gene, Oprm. Neuroscience V133.1 August 2005.
2. ↑ Waldhoer Maria, Bartlett Selena E., Whistler Jennifer L. Opioid Receptors. Annual Review of Biochemistry V73 March 2004,
3. ↑ "DOI:"P42866
4. ↑ Pan L., Xu J., Yu R., Xu M., Pan Y -X., Pasternak G.W. Identification and characterization of six new alternatively spliced variants of the human μ opioid receptor gene, Oprm. Neuroscience V133.1 August 2005.
5. ↑ Liao Dezhi, Lin Hang, Law Ping Yee, Loh Horace H. Mu-opioid receptors modulate the stability of dendritic spines. Proceedings of the National Academy of Sciences of the United States December 2004
6. ↑ Watanabe Masahito, Maemura Kentaro, Kanbara Kiyoto, Tamayama Takumi, Hayasaki Hana, GABA and GABA Receptors in the Central Nervous System and Other Organs. International Review of Cytology 2002
7. ↑ Liao Dezhi, Lin Hang, Law Ping Yee, Loh Horace H. Mu-opioid receptors modulate the stability of dendritic spines. Proceedings of the National Academy of Sciences of the United States December 2004
8. ↑ Manglik Aashish, Kruse Andrew C., Kbilka Tong Sun, Thian Foon Sun, Mathiesen Jesper M., Sunahara Roger K., Pardo Leonardo, Weis William L., Kobilka Brain K., Granier Sebastien. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature V485 May 2012
9. ↑ Manglik Aashish, Kruse Andrew C., Kbilka Tong Sun, Thian Foon Sun, Mathiesen Jesper M., Sunahara Roger K., Pardo Leonardo, Weis William L., Kobilka Brain K., Granier Sebastien. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature V485 May 2012