Regulation of the slow afterhyperpolarization in enteric neurons by protein kinase A

The slow after-hyperpolarization (sAHP) following the action potential is an important determinant of the firing patterns of enteric neurons. The channel responsible for the sAHP thus serves as a critical control point at which neurotransmitters and inflammatory mediators modulate gut motility. Many of these receptor-evoked pathways are known to inhibit the sAHP and, thus, excite enteric neurons. They act through protein kinase A (PKA) which is a strong inhibitor of the sAHP current while protein phosphatases enhance the current. Increasing evidence suggests that the sAHP is mediated by the opening of intermediate-conductance Ca-activated potassium (IK) channels. This neuronal IK channel, previously known to be expressed in a variety of non-excitable cells, is strongly influenced by protein kinases. Investigation of the molecular basis for the modulation of IK channels by protein phosphorylation indicates that there are multiple mechanisms of channel control. Inhibition of channel activity by PKA involves phosphorylation sites located within the calmodulin-binding domain of the channel. The localization of these sites within the region involved in Ca2 + activation suggests that PKA-mediated phosphorylation of the channel opposes the conformational changes caused by binding of Ca/calmodulin, which would otherwise lead to opening of the channel. We suggest that the channel exists as a macromolecular complex involving calmodulin, protein kinases, protein phosphatase and possibly other proteins. The regulation of the channel through kinases and phophatases results in exquisite control of neuronal firing and subsequent modulation of enteric reflexes.