Search

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism. Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism. [ABSTRACT FROM AUTHOR]

Oligodendrocytes produce myelin, which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions, myelin is damaged, resulting in mental and physical disabilities. Recent evidence suggests that oligodendrocyte damage during ischaemia can be mediated by Transient Receptor Potential Ankyrin-1 (TRPA1), whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is constitutively active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential (CAP). Conversely, TRPA1 agonists reduce the size of the optic nerve CAP in an A-967079-sensitive manner. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of CAPs during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during, or after OGD, indicating that the TRPA1-mediated damage is occurring during both ischaemia and recovery, but importantly, that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating many white matter diseases. [ABSTRACT FROM AUTHOR]

Oligodendrocytes wrap myelin around axons to increase the conduction velocity of the action potential. Failure to myelinate, damage to myelin, or loss of oligodendrocytes leads to severe debilitating mental and physical impairment. Myelin damage during ischaemia was previously thought to be mainly by activation of oligodendrocyte ionotropic glutamate receptors, which allow a detrimental influx of calcium. By patchclamping oligodendrocytes to record their currents, while imaging their intracellular ions with ion sensitive dyes, and applying solution which mimics the conditions found in ischaemia, we found that most of the glutamate-mediated current into oligodendrocytes is indirect and caused by a rise in extracellular potassium concentration. Oligodendrocytes respond to raised extracellular potassium concentrations by acidifying their cytosol; this in turn activates TRP channels, which we identified as mainly being TRPA1, because the response is largely inhibited by specific TRPA1 channel blockers (HC 030031 and A965079), and genetic TRPA1 knock out. The calcium influx through the proton-activated TRP channels leads to separation of myelin lamellae, and conduction block, which may contribute to the decrease in conductance of the action potential observed during ischaemia. As such TRPA1 represents a possible new therapeutic target that may decrease white matter damage in ischaemia. [ABSTRACT FROM AUTHOR]