Neurokinin B is a neuropeptide, a chemical messenger used by neurons for communication. Encoded by the TAC3 gene in humans, it is a member of the tachykinin family of peptides. While produced in various parts of the nervous system, its functions are most understood within the hypothalamus, a region at the base of the brain. The structure and function of Neurokinin B are conserved across most mammalian species, highlighting its biological importance.
Primary Function in the Brain
Within the brain, Neurokinin B (NKB) operates as part of a control system in the hypothalamus. It is produced by a group of neurons known as KNDy neurons, an acronym for the three neuropeptides they co-express: Kisspeptin, Neurokinin B, and Dynorphin. These KNDy neurons are in a region called the arcuate nucleus and function as the central pulse generator for Gonadotropin-releasing hormone (GnRH). This rhythmic secretion of GnRH is fundamental for reproductive health.
The interaction between the three neuropeptides within KNDy neurons creates a finely tuned rhythm. NKB acts as the accelerator in this system. When released, NKB binds to its receptor, the neurokinin 3 receptor (NK3R), on neighboring KNDy neurons, stimulating them. This leads to a burst of activity and the release of kisspeptin, which then activates GnRH neurons, causing a pulse of GnRH to be released.
Following this burst of activity, the third neuropeptide, dynorphin, acts as the brake. Dynorphin is released and binds to its own receptors on the KNDy neurons, inhibiting their activity and terminating the pulse. This interplay between NKB starting the pulse and dynorphin stopping it ensures the rhythmic release of kisspeptin and, consequently, GnRH. This mechanism functions as an internal clock, generating the hormonal patterns required for reproductive processes.
Role in Puberty and Fertility
The activation of the KNDy neural system is a significant event marking the onset of puberty. Before puberty, this system is dormant, but as puberty approaches, an increase in NKB signaling helps to awaken these neurons. This initiates the pulsatile release of GnRH, which travels to the pituitary gland to stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones then act on the gonads to stimulate sex hormone production, driving the development of secondary sexual characteristics.
The importance of NKB in this process is underscored by human genetics. Individuals with inactivating mutations in the gene for NKB (TAC3) or its receptor (TACR3) often fail to undergo puberty, a condition known as congenital hypogonadotropic hypogonadism. This demonstrates that functional NKB signaling is a prerequisite for initiating the reproductive axis.
Once puberty is complete, the continued activity of the KNDy pulse generator is necessary for maintaining fertility. In females, the rhythmic release of GnRH and subsequent pituitary hormones orchestrates the monthly menstrual cycle, including ovulation. The pulsatile nature of the hormonal signals, driven by the NKB-dynorphin interplay, ensures that follicular development, ovulation, and uterine preparation occur in a coordinated manner. Any disruption to this rhythm can lead to irregular cycles and impaired fertility.
Connection to Menopausal Symptoms
During menopause, ovarian function declines, leading to a significant drop in estrogen production. Estrogen normally provides a powerful negative feedback signal to the KNDy neurons, keeping their activity in check. When estrogen levels fall, this inhibitory signal is lost, causing the KNDy neurons to become overactive and enlarged, a state known as hypertrophy.
This hyperactivity of KNDy neurons is a direct cause of menopausal vasomotor symptoms, particularly hot flashes and night sweats. The arcuate nucleus, where KNDy neurons are located, is situated near the brain’s primary thermoregulatory center. The excessive firing of these overstimulated KNDy neurons is thought to disrupt the normal function of this neighboring temperature-control center.
The overproduction of NKB during this state is a key part of the problem. The intense signaling from hypertrophied KNDy neurons sends a false signal to the thermoregulatory center, tricking it into believing the body is overheating. In response, the body initiates heat-dissipation mechanisms, such as peripheral vasodilation and sweating. This cascade of events is experienced as a sudden wave of heat, known as a hot flash.
Therapeutic Targeting of Neurokinin B
The understanding of NKB’s role in hot flashes has led to the development of a new class of non-hormonal treatments for menopausal symptoms. These drugs are known as NK3 receptor antagonists. They work by selectively blocking the neurokinin 3 receptor, which NKB binds to. By occupying this receptor, the antagonists prevent the excessive NKB from overactive KNDy neurons from stimulating its target.
This therapeutic approach calms the hyperactivity within the KNDy system without replacing the body’s lost estrogen. By blocking the NKB signal, these drugs prevent the disruption of the brain’s thermoregulatory center, reducing the frequency and severity of hot flashes and night sweats. This mechanism targets the specific neural pathway responsible for the symptoms.
This targeted approach has led to the approval of new medications. For example, the U.S. Food and Drug Administration (FDA) approved fezolinetant in 2023 for the treatment of moderate to severe vasomotor symptoms associated with menopause. Another drug, elinzanetant, which targets both the NK3 and NK1 receptors, has also shown promising results in clinical trials. These developments represent a significant advancement in treatment.