NF1 Is an Effector and Regulator of the GPCR Signaling in the Nervous System

Principal Investigator: MARTEMYANOV, KIRILL
Program: NFRP
Proposal Number: NF130030
Award Number: W81XWH-14-1-0074
Funding Mechanism: New Investigator Award
Partnering Awards:
Award Amount: $755,991.00


Neurofibromatosis type 1 (NF1) is a devastating disorder that affects approximately 1 out of 3,000 people. In addition to developing tumors, NF1 patients suffer from prominent neuropsychiatric symptoms that include cognitive impairments, motor coordination problems, attention difficulties, and pain. The disease is caused by mutations in the gene that encodes neurofibromin protein, NF1. Research on NF1 has established that this protein plays an important role in the nervous system by regulating key cellular signaling pathways. However, the manner by which NF1 regulates these signaling reactions and neurotransmitter systems that are affected by the NF1 loss are poorly understood.

We have made an unexpected observation that NF1 associates with the key protein involved in transmission of signals of membrane receptors called G Protein Coupled Receptors (GPCR). Signaling via GPCRs underlies a variety of fundamental neuronal processes including neurotransmitter action, pain perception, cognition, and memory. Based on the preliminary observations, we propose the hypothesis that NF1 regulates key signaling reactions in the neurons by mediating GPCR action.

Our proposed experiments will test this hypothesis by exploring this novel GPCR-NF1 connection using a mouse model of neurofibromatosis interrogated by a variety of cell biological and biochemical approaches aimed at elucidating precise molecular mechanisms. With close to 50% of all clinically approved drugs on the market targeting GPCR systems, we expect that better understanding of the role that NF1 plays in controlling these systems will pave the way to the adaptation of already approved medications to the treatment of neurofibromatosis. In particular, multiple lines of evidence implicate the intersecting points between GPCR and NF1 in pain perception and memory formation. This gives us hope that in the long run, this line of research will help combat pain and neuropsychiatric manifestations of the disease and improve the quality of patients' lives.