Cloning and functional expression of a cDNA from the human cerebellum revealed a parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor protein of 593 amino acids, identical in sequence to the PTH/PTHrP receptor of the human kidney and an osteoblast-like cell line (Schipani et al., Endocrinology, 132 (1993) 2157-2165). Expression of mRNA hybridizing with the cloned cDNA, indistinguishable in size on Northern blots from a 2.3 kb transcript in kidney and liver, was detected in eight brain areas. In situ hybridization histochemistry in rat brain tissue sections revealed predominant signals in the Purkinje cell layer of the cerebellum and in the mesencephalic nucleus of the trigeminal nerve. In human neuroblastoma (SK-N-MC) cells, stably transfected with the cloned cDNA, hPTH(1-84) and hPTH(1-34) displaced binding of 125 pM [125I][Tyr36]chPTHrP(1-36) to the PTH/PTHrP receptor with IC50 values of 4.0 +/- 0.6 nM and 2.00 +/- 0.08 nM, and stimulated cyclic AMP accumulation with EC50 values of 0.19 +/- 0.06 nM and 0.09 +/- 0.01 nM, respectively. 16 out of 48 cells responded to 100 nM hPTH(1-34) with a 2-10-fold transient increase of cytosolic free calcium concentrations. In conclusion, a PTH/PTHrP receptor, identified in the human cerebellum, has the primary structure of the corresponding receptors of kidney and bone. Expression in human neuroblastoma SK-N-MC cells revealed functional properties indistinguishable from those of non-neuronal tissues. The widespread distribution of PTHrP and its receptor in brain implies biological functions remaining to be elucidated.