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Calcitonin (CT) Rapidly Increases Na⁺/H⁺ Exchange and Metabolic Acid Production: Effects Mediated Selectively by the C1a CT Receptor Isoform

CIHR Group in Skeletal Remodeling, Department of Physiology, Division of Oral Biology (A.S., S.J.D.), and Department of Pharmacology & Toxicology (P.C.), Faculty of Medicine & Dentistry, The University of Western Ontario, London, Canada N6A 5C1; and Departments of Cell Biology and Orthopedics and the Yale Cancer Center (W.C.H., R.B.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Dr. S. J. Dixon, Department of Physiology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail: jeff.dixon{at}fmd.uwo.ca

Two isoforms of the calcitonin receptor are expressed in rabbit: the common C1a isoform and the calcitonin receptor e13 isoform, which has a deletion in the seventh transmembrane domain. Using microphysiometry, we investigated the effects of calcitonin on proton efflux from HEK293 cells stably transfected with C1a, calcitonin receptor e13, or empty vector. In C1a-expressing cells only, calcitonin rapidly induced a biphasic elevation in proton efflux consisting of an initial transient and a sustained plateau, accompanied by an increase in lactate efflux. Inhibitors of Na⁺/H⁺ exchange abolished only the initial transient, whereas removal of extracellular glucose abolished only the sustained plateau. These data suggest that activation of Na⁺/H⁺ exchange mediates the initial transient, whereas increased glucose metabolism underlies the sustained plateau. Because both receptor isoforms activate adenylyl cyclase, the lack of effect of calcitonin on proton efflux from calcitonin receptor e13-expressing cells argued against involvement of cAMP in activating proton efflux. Similarly, studies involving elevation or buffering of cytosolic free Ca²⁺ concentration argued against involvement of Ca²⁺. Activation of PKC mimicked the plateau phase of calcitonin-induced proton efflux from C1a cells, whereas inhibition or depletion of PKC suppressed it. Activation of proton transport and production are novel cellular responses to calcitonin, mediated selectively by the C1a receptor isoform via a mechanism involving PKC.

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