Receptor‐mediated action of nicotine in human skin

In this issue, p. 731, Drs Craig G. Burkhart and Craig N. Burkhart review published reports of successful use of nicotine in some dermatologic and nondermatologic conditions. They rightfully conclude that analog drugs which would avoid inherent health hazards of nicotine may be developed in the future, in order to improve the treatment for speci®c conditions without the risk of other major health problems seen with nicotine. It should be emphasized that identi®cation of the receptor-mediated pathways mediating nicotine effects in particular skin cell types will open a door for designing speci®c treatment regimens of skin problems using receptor-selective drugs. In the skin, nicotine mimics effects of acetylcholine (ACh) ± the natural agonist of both the nicotinic-type ACh receptors (nAChRs), which are sensitive to nicotine, and the muscarinic-type ACh receptors (mAChRs), which are not sensitive to the pharmacologic doses of nicotine. ACh is produced by practically all types of living cells and is remarkably abundant in human skin. It has become evident that a single cytotransmitter, ACh, can regulate tissue homeostasis in an autocrine and paracrine fashion by exhibiting a plethora of biological effects on different cell types. Current research results indicate that biological effects of ACh in the skin are ®nely tuned to regulation of each phase of the cell cycle via the intracellular signaling pathway(s) coupled by each particular type of ACh receptor. Binding of ACh to the cell membrane simultaneously elicits several diverse biochemical events the ``bological sum'' of which, taken together with cumulative effects of other hormonal and environmental stimuli, determines a distinct change in the cell cycle. The nAChRs are classical representatives of a large superfamily of ligand-gated ion channel proteins, or ionotropic receptors, mediating the in ̄ux of Na and Ca and ef ̄ux of K. A large variety of second and third messengers, such as Ca, nitric oxide, prostacyclin, cytokines and growth factors, can subserve nicotinic effects in non-neuronal cells. At least nine a subunits, designated a2±a10, and three b subunits, b2±b4, have been identi®ed to date in nonmuscle cells, whereas the myocytes express a1, b1 as well as g, s, and e, subunits. Each of a7, a8, and a9 subunits is capable of forming functional homomeric nAChR channels. The heteromeric nAChR channels can be composed of the a2, a3, a4, a5, a6, b2, b3 and b4 subunits, e.g. a3b2(b4) 6 a5, and a9 subunit can form a heteromeric channel with a10 subunit. The differences in subunit composition of nAChRs determine the functional and pharmacologic characteristics of the ion channels formed. Nicotine acts as an agonist at all nAChR types, except for a9-made channels, where its effect is antagonist-like and the downstream signaling can include both the ionic and the metabotropic events. We have recently cloned the human homolog of rat a9 nAChR from human keratinocytes and showed that this receptor is targeted by pemphigus vulgaris autoantibody. This receptor is unique because it represents a novel human ionotropicand-metabotropic receptor/Ca channel. Given the paramount importance of Ca metabolism for keratinocyte development, the drugs that can selectively ligate a9 nAChR, or other Ca-permeable nAChR types expressed by human keratinocytes, are expected to modulate vital cell functions in a predictable fashion. The plethora of nicotine effects in the mucocutaneous tissues stems from the fact that different nAChR subtypes are expressed by a variety of locally present neuronal as well as non-neuronal cells, such as keratinocytes, ®broblasts, endothelial cells, melanocytes, and bone marrow-derived cells. The differences in the types of nAChRs expressed by individual cell types diversify the