So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

https://science.sciencemag.org/content/sci/233/4761/305.full.pdf

Studies and perspectives of protein kinase C

Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Dopamine Receptors: From Structure to Function

[This corrects the article on p. 100 in vol. 41.].

Energy conservation in chemotrophic anaerobic bacteria.

The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.

https://science.sciencemag.org/content/sci/250/4986/1429.full.pdf

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons

http://www.jbc.org/content/237/1/89.full.pdf

Aromatic l-Amino Acid Decarboxylase

Studies on the chemical nature of clostridial ferredoxin.

Development of a rapid and sensitive radioassay has permitted study of the conversion of tryptophan to 5-hydroxytryptophan in mammalian tissues. Of normal tissues examined, beef and rat pineal gland contained the highest activity. This is the first direct demonstration of tryptophan hydroxylase in this hydroxyindole-rich tissue. Rat and rabbit brainstem and human carcinoid tumor also had quantities of enzyme that could be measured easily. The reaction requires a reduced pteridine and oxygen and is inhibired by Para-Chorophenylalanine.

https://science.sciencemag.org/content/sci/155/3759/217.full.pdf

Tryptophan Hydroxylation: Measurement in Pineal Gland, Brainstem, and Carcinoid Tumor

Administration of the specific serotonin depletor p-chlorophenylalanine to rats results in marked inhibition of tryptophan hydroxylase of the brain. The enzyme inhibition can be correlated with and is assumed to be responsible for brain serotonin depletion. Although p-chlorophenylalanine is a competitive inhibitor of tryptophan hydroxylase in vitro, it causes an irreversible inactivation of the enzyme in vivo. The findings also support the conclusion that tryptophan hydroxylation is the rate-limiting enzymic step in serotonin biosynthesis.

Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin.

The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136±18 (SE) and 37.4±5.3 μg/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195±20 μg/day (P<0.01) whereas urinary norepinephrine decreased to 21.1±3.0 μg/day (P<0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18±0.22 to 2.79±0.19 μg/20 min, P<0.01), but decreased plasma dopamine-β-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and p-aminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

/pdf/effects-of-dietary-sodium-and-of-acute-saline-infusion-on-12gkivk8bs.pdf

Walter Lovenberg

Papers

Aromatic l-Amino Acid Decarboxylase

Studies on the chemical nature of clostridial ferredoxin.

Tryptophan Hydroxylation: Measurement in Pineal Gland, Brainstem, and Carcinoid Tumor

Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin.

Effects of Dietary Sodium and of Acute Saline Infusion on the Interrelationship between Dopamine Excretion and Adrenergic Activity in Man