Eccrine (atrichial) sweat glands are large, active cutaneous endorgans vital to human thermal and fluid homeostasis, but regional overactivity of these glands can lead to focal hyperhidrosis. Eccrine sweat glands can expulse over 10 nl/min in a single isolated gland and as much as 3.7 l/h systemically in response to thermal and non-thermal stimuli (1, S1, S2). How do these glands produce such copious secretions? Sweating involves a two-stage process of first producing an isotonic primary solution within the bulbous coiled region of the gland and then modifying (primarily via reabsorbing NaCl) this fluid within the ductal portion as it travels to the skin surface. Thus, production of this primary fluid requires careful scrutiny to understand hyperhidrosis. Epithelial transport in these glands appears to be primarily mediated via clear (agranular) cells, which are also the proposed cell type associated with hyperhidrosis (2). In the current understanding of clear cell function, Cl À is transported through the clear cell, Na+ is transported through tight junctions via a transepithelial voltage gradient, and finally water is pulled through aquaporin channels via osmotic forces. Thus, Cl À is a principal player in the formation of the isotonic primary solution. It is, however, another ion, Ca2+, that appears to be the primary regulator within clear cells.

The majority of sudorific agonists (eg acetylcholine, norepinephrine via a1-adrenergic receptors and ATP) increase cytosolic Ca2+ via efflux from cellular stores and influx from extracellular fluid. Ca2+ release from intracellular stores is derived via IP3-activated Ca2+ and Ca2+-induced Ca2+ release channels. The influx into the clear cells is a bit more complex, likely involving TRPV1, store-operated Ca2+ entry (Orai1 and TRPC1) and L-type voltagegated Ca2+ channels (3–5, S3). Highlighting the importance of Ca2+ influx, secretions are abated when isolated glands are placed into Ca2+-free bath (S4, S5), and recent in vivo experiments identified right shifts in the cholinergic agonist to sweating relation with both EDTA (used as an interstitial Ca2+ chelator) and verapamil (L-type channel blocker)(4). The regulatory role of cytosolic Ca2+ is to activate many of the ion channels involved in epithelial transport.