Limits...
Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways.

Blackshaw LA, Page AJ, Young RL - Front Neurosci (2011)

Bottom Line: All mGluR are found in the mammalian nervous system but some are absent from sensory neurons.This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators.There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.

View Article: PubMed Central - PubMed

Affiliation: Nerve Gut Research Laboratory, Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital Adelaide, SA, Australia.

ABSTRACT
Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.

No MeSH data available.


Related in: MedlinePlus

Classification of Glutamate receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3066463&req=5

Figure 1: Classification of Glutamate receptors.

Mentions: Glutamate (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS). It also acts to modulate synaptic transmission both pre- and post-synaptically. These actions are mediated via a large range of ionotropic (iGluR, NMDA, AMPA, and kainate), and metabotropic (mGluR, group I, II, III) receptors. iGluR are directly coupled to cation channels, and their activation evokes fast synaptic events which may lead to longer-term changes in excitability (Bleakman and Lodge, 1998; Yamakura and Shimoji, 1999). mGluR exist as eight subtypes of G-protein coupled receptor: Group I (mGluR1 and 5) are excitatory and are believed to act mainly via Gαq/phospholipase C. Group II (mGluR2 and 3), and III (mGluR4, 6, 7, and 8) inhibit adenylate cyclase and alter cation currents via Gαi and Gβγ subunits respectively (Conn and Pin, 1997; Schoepp et al., 1999; Figure 1).


Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways.

Blackshaw LA, Page AJ, Young RL - Front Neurosci (2011)

Classification of Glutamate receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3066463&req=5

Figure 1: Classification of Glutamate receptors.
Mentions: Glutamate (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS). It also acts to modulate synaptic transmission both pre- and post-synaptically. These actions are mediated via a large range of ionotropic (iGluR, NMDA, AMPA, and kainate), and metabotropic (mGluR, group I, II, III) receptors. iGluR are directly coupled to cation channels, and their activation evokes fast synaptic events which may lead to longer-term changes in excitability (Bleakman and Lodge, 1998; Yamakura and Shimoji, 1999). mGluR exist as eight subtypes of G-protein coupled receptor: Group I (mGluR1 and 5) are excitatory and are believed to act mainly via Gαq/phospholipase C. Group II (mGluR2 and 3), and III (mGluR4, 6, 7, and 8) inhibit adenylate cyclase and alter cation currents via Gαi and Gβγ subunits respectively (Conn and Pin, 1997; Schoepp et al., 1999; Figure 1).

Bottom Line: All mGluR are found in the mammalian nervous system but some are absent from sensory neurons.This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators.There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.

View Article: PubMed Central - PubMed

Affiliation: Nerve Gut Research Laboratory, Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital Adelaide, SA, Australia.

ABSTRACT
Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.

No MeSH data available.


Related in: MedlinePlus