G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions (including various autocrine, paracrine and endocrine processes). They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups. We use the term clan to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [1]. The currently known clan members include the rhodopsin-like GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating pheromone receptors, and the metabotropic glutamate receptor family. There is a specialized database for GPCRs: http://www.gpcr.org/7tm/.

The rhodopsin-like GPCRs themselves represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [2, 3, 4].

Neuropeptide FF (and neuropeptide AF, which is also derived from the same precursor) belong to a family of neuropeptides containing an RF-amide motif at their C-terminus. Neuropeptide FF (NPFF) is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation [5]. Two G protein-coupled receptors for NPFF have been identified; both are expressed in the central nervous system and couple to Gi proteins to inhibit adenylyl cyclase [6, 7].

The type 1 neuropeptide FF receptor is expressed at highest levels in the hypothalamus, with moderate expression in the thalamus, midbrain, medulla oblongata, testis and eye [8].