Carbohydrate ingestion reduces skeletal muscle acetylcarnitine availability but has no effect on substrate phosphorylation at the onset of exercise in man

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Abstract
The M-type potassium current (IM) plays a dominant role in regulating membrane excitability and is modulated by many neurotransmitters. However, except in the case of bradykinin, the signal transduction pathways involved in M-channel modulation have not been fully elucidated. The channels underlying IM are produced by the coassembly of KCNQ2 and KCNQ3 channel subunits and can be expressed in heterologous systems where they can be modulated by several neurotransmitter receptors including histamine H1 receptors. In HEK293T cells, histamine acting via transiently expressed H1R produced a strong inhibition of recombinant M-channels but had no overt effects on the voltage dependence or voltage range of IM activation. In addition, the modulation of IM by histamine was not voltage sensitive, whereas channel gating, particularly deactivation, was accelerated by histamine. Non-hydrolysable guanine nucleotide analogues (GDP-β-S and GTP-γ-S) and pertussis toxin (PTX) treatment demonstrated the involvement of a PTX-insensitive G protein in the signal transduction pathway mediating histamine-induced IM modulation. Abrogation of the histamine-induced modulation of IM by expression of a C-terminal construct of phospholipase C (PLC-β1-ct), which buffers activated Gαq/11 subunits, implicates this G protein α subunit in the modulatory pathway. On the other hand, abrogation of the histamine-induced modulation of IM by expression of two constructs which buffer free βγ subunits, transducin (Gαt) and a C-terminal construct of a G protein receptor kinase (MAS-GRK2-ct), implicates βγ dimers in the modulatory pathway. These findings demonstrate that histamine modulates recombinant M-channels in HEK293T cells via a PTX-insensitive G protein, probably Gαq/11, in a similar manner to a number of other G protein-coupled receptors. However, histamine-induced IM modulation in HEK293T cells is novel in that βγ subunits in addition to Gαq/11 subunits appear to be involved in the modulation of KCNQ2/3 channel currents.

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