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Abstract
Pasteurella multocida toxin (PMT) activates the G-proteins Gαi(1-3), Gαq, Gα11, Gα12 and Gα13 by deamidation of specific glutamine residues. A number of these alpha subunits have signalling roles in neurones. Hence we studied the action of this toxin on rat superior cervical ganglion (SCG) neurones and NG108-15 neuronal cells. Both Gαq and Gα11 could be identified in SCGs with immunocytochemistry. PMT had no direct action on Kv7 or Cav2 channels in SCGs. However PMT treatment enhanced muscarinic receptor mediated inhibition of M-current (Kv7.2 + 7. 3) as measured by a 19-fold leftward shift in the oxotremorine-M concentration–inhibition curve. Agonists of other receptors, such as bradykinin or angiotensin, that inhibit M-current did not produce this effect. However the amount of PIP2 hydrolysis could be enhanced by PMT for all three agonists. In a transduction system in SCGs that is unlikely to be affected by PMT, Go mediated inhibition of calcium current, PMT was ineffective whereas the response was blocked by pertussis toxin as expected.M1 muscarinic receptor evoked calcium mobilisation in transformed NG108-15 cells was enhanced by PMT. The calcium rises evoked by uridine triphosphate acting on endogenous P2Y2 receptors in NG108-15 cells were enhanced by PMT. The time and concentration dependence of the PMT effect was different for the resting calcium compared to the calcium rise produced by activation of P2Y2 receptors. PMT's action on these neuronal cells would suggest that if it got into the brain, symptoms of a hyperexcitable nature would be seen, such as seizures.
Highlights
Pasteurella multocida infections in humans are rare and if they occur it is usually due to contamination from a domestic animal
In NG108-15 cells transfected with the gene for M1 muscarinic receptors the calcium mobilisation was enhanced as it was for endogenous purinergic P2Y2 receptors (Figs. 7 and 8)
We have demonstrated in two cell types that the P. multocida toxin (PMT) C1165S mutant does not significantly shift the concentration inhibition curves for muscarinic receptor inhibition of Kv7 (M)-current in sympathetic ganglia (SCG) nor does it enhance the muscarinic receptor evoked calcium rise in NG108-15 cells (Fig. 7)
Summary
Pasteurella multocida infections in humans are rare and if they occur it is usually due to contamination from a domestic animal. Of further concern is the possible link between the P. multocida infection and cancer (Lax, 2012). The toxigenic status of the isolates linked with neurological infections is not known. There is very limited knowledge on the effects of this toxin on neurones or neuronal cells, with the exception of the work of Brothers et al (2011) on membrane interactions of PMT in mouse neuroblastoma  rat glioma hybrid (NG108-15) cells. We have investigated the cellular effect of PMT on primary neurones in culture (rat superior cervical sympathetic ganglion (SCG) cells) and a differentiated neuronal cell line (NG108-15)
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