TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels.
Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. Electronic address:
Objective: Antagonism of the muscarinic acetylcholine type 1 receptor (MR) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in MR antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.
Methods: Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and MR antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7).
Transient Receptor Potential (TRP) ion channels like Vanilloid 1 (TRPV1) and Melastatin 3 (TRPM3) are nonselective cation channels expressed in primary sensory neurons and peripheral nerve endings, which are located in cholesterol- and sphingolipid-rich membrane lipid raft regions and have important roles in pain processing. Besides TRP ion channels a wide variety of voltage-gated ion channels were also described in the membrane raft regions of neuronal cells. Here we investigated the effects of lipid raft disruption by methyl-beta-cyclodextrin (MCD) and sphingomyelinase (SMase) on TRPV1, TRPM3 and voltage-gated L-type Ca channel activation in cultured trigeminal neurons and sensory nerve terminals of the trachea.
The TRPM3 gene, part of the transient receptor potential (TRP) cation channel family, plays crucial roles in sensory perception and ion transport. Mutations in TRPM3 are linked to a range of neurological and developmental disorders. The c.
Sensory neurons serve to receive and transmit a wide range of information about the conditions of the world around us as well as the external and internal state of our body. Sensitisation of these nerve cells, i.e.
Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it.
