Endocrine Abstracts

Prokineticin receptors (PKR1 and PKR2) are GPCRs that belong to neuropeptide Y receptor class. They exert their biological functions binding two structurally related peptides (Bv8 or PK2 and EG-VEGF orr PK1). Intensive research over the past few years has shown that PKs/PKRs signalling modulates neuronal survival and neurogenesis, hypothalamic hormone secretion, nociception, circadian rhythm and complex behaviours, such as feeding and drinking. It also promotes angiogenesis in steroidogenic tissues and reproductive organs, hematopoiesis and immune response.

A growing body of evidence points to the fact that GPCRs exist as homo- or heterodimers but the functional impact for many of these dimers still remains unclear.

The study’s aim was to confirm PKR2 homodimerization, to indentify the homodimerization interface and to assess PKR1-PKR2 heterodimerization. Techniques namely bioluminescence resonance energy transfer (BRET) were used to study receptor-receptor interactions in live cells in real time. The interaction site of PKR2 homodimer was assessed by use of receptor fragments corresponding to TM1-5, TM1-4, TM1-7 and TM6-7. These were also employed to determine the role of PKR2 homodimerization in receptor targeting to the membrane.

Two missense mutations (P290S and L173R) within transmembrane domains of PKR2 sequence were also studied. It has been demonstrated that these PKR2 mutants can cause the Kallmann syndrome phenotype, which combines hypogonadism, due to gonadotropin-releasing hormone deficiency, and anosmia or hyposmia, due to defective olfactory bulb morphogenesis. We investigated the effects of these mutations on cell surface targeting and dimerization of both mutated and wild-type receptors.

Given the importance of dimerization in receptor synthesis and cell surface targeting, the work obtained can provide a framework for interpretation of results concerning the PKR2 mutants associated with Kallmann syndrome.