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Abstract
Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation.
Highlights
Acetylcholine (ACh) is mainly known as a neurotransmitter, but ACh and its receptors act as mediators of cell communication in non-neuronal cells
We have here characterized the role of epidermal growth factor receptor (EGFR) in extracellular signal regulated kinase (ERK) activation by cholinergic stimuli in HaCaT keratinocytes
To study if a cholinergic stimulus leads to activation of ERK and Akt, HaCaT cells were stimulated for 30 min with the cholinergic agonist carbachol (CCh, 1 mM), EGF (16 nM) or nicotine (100 μM), and the activation of Akt and ERK was analyzed with phospho-specific antibodies (Figure 1A)
Summary
Acetylcholine (ACh) is mainly known as a neurotransmitter, but ACh and its receptors act as mediators of cell communication in non-neuronal cells. The existence and importance of non-neuronal cholinergic systems has gained high attention and acceptance over the last two decades (reviewed in [1,2]). Two classes of ACh receptors mediate the effects of cholinergic stimulation. The nicotinic acetylcholine receptors (nAChR) are ion channels, whereas the muscarinic receptors (mAChR) belong to the family of G protein coupled receptors (GPCR) which are coupled to heterotrimeric guanine nucleotide binding proteins (G proteins). The mAChR family consists of five receptor subtypes referred to as M1, M2, M3, M4 and M5 receptors. Depending on the G protein type they are associated with, they activate different signal transduction pathways.
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