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ls. We used the toxin MT that is a highly selective irreversible allosteric antagonist of M mAChR, the antagonist DAMP that has fold higher affinity for M M than for M M mAChRs, and also carried out RT PCR to determine the levels of each mAChR subtype mRNA. We first confirmed the effects of MT and DAMP in CHO K cells expressing the M or M mAChRs. MT pre treatment completely Doxorubicin blocked ACh stimulated Ca Doxorubicin release in cells expressing theM receptor , but had no effect on the response to activation of M mAChRs . DAMP addition caused a drop in basal Ca release and a right shift of the concentration response curves to ACh in both cell types, with estimated pKB values of and . In L cells, MT had no significant effect on Ca responses, while DAMP caused a substantial right shift of the ACh concentration response curve .
The pKB of DAMP in L cells was , comparable with the value observed in M mAChR transfected CHO K cells. RT PCR showed detectable bands of varying intensity for M mRNA in three separate samples from differentiated L cells, whereas one sample from the differentiated cells displayed a very weak M Imatinib band . M primers gave a weak band of the correct size, but the intensity was greater in undifferentiated than in differentiated L cells. There were no bands at all detected for M mRNA. The failure of MT to block Ca release in L cells provides strong evidence that the M mAChR and not the M mAChR is the major functional mAChR subtype in L cells. In addition, the M mAChR RT PCR results are consistent with the earlier demonstration that mAChRs can be detected by a selective muscarinic radioligand only in differentiated L cells .
Insulin stimulated glucose uptake is severely impaired in type diabetes, and there is considerable interest in the identification of insulin independent activators of glucose uptake. NSCLC GPCRs represent the largest class of drug targets with ～ of all currently marketed drugs aimed at GPCRs, and are an attractive target for the treatment of obesity and type diabetes .We and others have previously shown that activation of adrenoceptors can increase glucose uptake in skeletal muscle , adipocytes and astrocytes through a variety of mechanisms, including utilisation of components of the insulin signalling pathway and activation of AMPK. In L skeletal muscle cells, activation of several GPCRs has been shown previously to increase glucose uptake, including HTA receptors , and opioid receptors , adrenoceptors and adrenoceptors .
Here, we demonstrate that muscarinic ACh receptor agonists can regulate glucose homeostasis in skeletal muscle, increasing glucose uptake with efficacy similar to that of insulin. Glucose uptake in skeletal muscle occurs by translocation Imatinib of GLUT containing vesicles to the cell surface through two main pathways: insulin stimulated activation of PI kinase and subsequent activation of Akt and atypical protein kinase C, or by activation of AMPK. AMPK is a target for the treatment of type diabetes, with drugs used clinically to treat type diabetes acting partly through this pathway . Several GPCRs have been shown to exert some of their actions on glucose uptake by modulation of AMPK activity .
For example, adrenoceptor activation increases glucose uptake through AMPK in L cells and activation of adrenoceptors in skeletal muscle contributes to some of the effects of leptin on skeletal muscle AMPK activity . In our study, inhibition of AMPK with Compound C had no significant effect Doxorubicin on insulin mediated glucose uptake , but did completely inhibit AICAR mediated glucose uptake. Acetylcholine, carbachol and oxotremorine M mediated glucose uptake was also completely blocked by Compound C, indicating that glucose uptake in response to mAChR stimulation in skeletal muscle cells involves AMPK activation. mAChR expression has previously been described in cultured rat skeletal muscle , rat L skeletal muscle cells and mouse CC skeletal muscle cells utilising a combination of radioligand binding assays and pharmacological studies.
However the muscarinic receptor Imatinib subtype present is not well defined. Earlier studies indicated that only the M receptor subtype occurs in L cells, as muscarinemediated IP accumulation is blocked by pirenzipine, an M selective antagonist, but not DAMP, an M M selective antagonist . However, in cultured rat skeletal muscle, there is evidence for M and M receptors Imatinib since both pirenzipine and DAMP antagonize carbachol mediated diacylglycerol generation . In our hands, the concentration response curve for ACh stimulated Ca release in L cells was shifted to the right by DAMP, but not affected by the M selective antagonist MT . The DAMP acts as a classical competitive antagonist, causing a fold decrease in ACh potency. We have also demonstrated that differentiated L skeletal muscle cells express primarily M receptor mRNA, consistent with radioligand binding studies showing thatmAChRs are present only in differentiated L cells, with a Bmax value , similar to that previously reported