The structure-energy landscape of NMDA receptor gating

…using single-molecule Forster resonance energy transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions. These results show kinetically and structurally distinct changes associated with apo, agonist-bound, and inhibited receptors linked by a linear mechanism of gating at this site. Furthermore, the smFRET data suggest that allosteric inhibition by zinc occurs by an uncoupling of the agonist-induced changes at the extracellular domains from the gating motions leading to an apo-like state, while dizocilpine, a pore blocker, stabilizes multiple closely packed transmembrane states.

Achiral glycine in position 6 of the gonadotropin releasing hormone (GnRH) decapeptide links the energy landscape from ecological variation to the stability of the 7 transmembrane states in the GnRH receptor to the creation of all biophysically constrained vertebrate biodiversity via feedback loops that link food odors and pheromones to the survival of all species on Earth. Organisms die without food and species become extinct when too many conspecifics die. The virus-driven degradation of messenger RNA, links mutations to all pathology and to death and the extinction of species.

Reported as: Molecule Movements Through Nerve Cells Could Lead to Multi-functional Drugs

The NMDA receptor is set of four protein subunits, each with four domains, and each of those domains has a particular function. Collectively, they span the cell membrane. Each subunit can have many “states,” or shapes, that regulate which electrical signals — and how many of them — pass through. The subunits sit on each side of the channel and activate when they bind both glutamate and glycine neurotransmitter ligands and trigger the signaling pathway that allows positively charged ions to pass into the cell.

The energy-dependent “states” are the functional shapes of receptors that link electrical signals to receptor-mediated behavior and to all biodiversity. Their function can be examined in the context of links from electrons to ecosystems via cryo-electron microscopy (cryo-EM).

All energy-dependent functions in all living genera link top-down causation from food energy-dependent feedback loops to the pheromone-controlled physiology of reproduction in species of microbes to survival of all species. For example, the effects of energy-dependent binding of glutamate and glycine neurotransmitter ligands to their substrates can be examined in the relatively simplistic context of this 2005 review of ecological variation and ecological adaptations.

Feedback loops link odor and pheromone signaling with reproduction

It appears that GnRH neurons integrate a variety of information about the internal state of the animal and its external environment. At least 10,000 neurons in 26 different brain areas appear to transmit signals directly to GnRH neurons. Among these are areas involved in odor and pheromone processing, sexual behavior, arousal, reward, and other functions. This suggests that GnRH neurons are poised to modulate reproductive physiology and behavior in accordance with the overall state of the animal.

These studies also indicate that GnRH neurons are likely to influence numerous brain functions. They appear to transmit signals to as many as 30,000 or more neurons in 34 brain areas, consistent with previous studies showing GnRH+ fibers and GnRH receptors in multiple brain regions (Badr and Pelletier, 1987; Jennes et al., 1988; Jennes et al., 1997). BL+ neurons likely to receive synaptic input from GnRH neurons were seen in areas associated with numerous different functions, including odor and pheromone processing, sexual behavior, appetite, defensive behavior, motor programs, and the relay of information to higher cortical areas. These results may reflect a strategy wherein GnRH neurons can modify diverse functions in order to coordinate the internal state of the animal and its behavior with reproduction in order to optimize reproductive success.

See for comparison to what is known about the feedback loops: Replication defective viral genomes exploit a cellular pro-survival mechanism to establish paramyxovirus persistence

My summary: Viral persistence (paramyxovirus persistence) and biophysically constrained epigenetically-effected viral latency require the energy-dependent fine-tuning of epigenesis and epistasis that links the pheromone-controlled physiology of reproduction from species of microbes to humans via what is known about soil microbes, fescue toxicosis, and the bull sperm microRNAome.

The most confusing representation of biophysically constrained energy-dependent epigenetically-effected top-down causation I have ever seen was reported as: Team shows how seemingly acute viral infections can persist

…our cells are wired to survive if they are engaged in an antiviral response…

One expert from the report, which is about the well known aspects of food energy-dependent autophagy attests to all the facts known to serious scientists. The facts refute the pseudoscientific nonsense touted by most theorists. For example, see the three articles that link the food energy-dependent pheromone-controlled physiology of reproduction in soil bacteria to all biodiversity in mammals.

  1. The Bull Sperm MicroRNAome and the Effect of Fescue Toxicosis on Sperm MicroRNA Expression
  2. Circulating microRNA as candidates for early embryonic viability in cattle
  3. The Breadth of Viruses in Human Semen 

The presence of viruses in semen is probably more widespread than currently appreciated, and the absence of virus in genital secretions should not be assumed for traditionally non–sexually transmitted viruses. The investigation of virus detection and persistence in semen across a range of viruses is useful for clinical and public health reasons, in particular for viruses that lead to high mortality or morbidity rates or to epidemics.

The presence of viruses in bacteria (bacteriophages) and in semen attests help to explain how serious scientists have linked the virus-driven theft of quantized energy from the degradation of messenger RNA to mutations and all pathology in all living genera. The facts can now be placed into the context of the fact that other organisms typically do not commit suicide. Energy-dependent autophagy typically links chirality to the protection of all cell types in all individuals of all species from suicide. That fact left me and others with questions about why people commit suicide.

See: Energy-dependent structure and function: Until death (2)

See also: Energy-dependent structure and function: Until death (3)

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