Evolution of neurotransmitter receptor systems

The presence of hormones, neurotransmitters, their receptors and biosynthetic and degradative enzymes is clearly not only associated with the present and the recent past but with the past several hundred million years. Evidence is mounting which indicates substantial conservation of protein structure and function of these receptors and enzymes over these tremendous periods of time. These findings indicate that the evolution and development of the nervous system was not dependent upon the formation of new or better transmitter substances, receptor proteins, transducers and effector proteins but involved better utilization of these highly developed elements in creating advanced and refined circuitry. This is not a new concept; it is one that is now substantiated by increasingly sophisticated studies. In a 1953 article discussing chemical aspects of evolution (Danielli, 1953) Danielli quotes Medawar, "... endocrine evolution is not an evolution of hormones but an evolution of the uses to which they are put; an evolution not, to put it crudely, of chemical formulae but of reactivities, reaction patterns and tissue competences." To also quote Danielli, "In terms of comparative biochemistry, one must ask to what extent the evolution of these reactivities, reaction patterns and competences is conditional upon the evolution of methods of synthesis of new proteins, etc., and to what extent the proteins, etc., are always within the synthetic competence of an organism. In the latter case evolution is the history of changing uses of molecules, and not of changing synthetic abilities." (Danielli, 1953). Figure 4 outlines a phylogenetic tree together with an indication of where evidence exists for both the enzymes that determine the biosynthesis and metabolism of the cholinergic and adrenergic transmitters and their specific cholinergic and adrenergic receptors. This figure illustrates a number of important points. For example, the evidence appears to show that the transmitters and their associated enzymes existed for a substantial period before their respective receptor proteins. While the transmitters and enzymes appear to exist in single cellular organisms, there is no solid evidence for the presence of adrenergic or cholinergic receptors until multicellular organisms where the receptors appear to be clearly associated with specific cellular and neuronal communication (Fig. 4). One can only speculate as to the possible role for acetylcholine and the catecholamine in single cell organisms.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serine/threonine protein phosphatases and synaptic inhibition regulate the expression of cholinergic-dependent plateau potentials

We previously identified cholinergic-dependent plateau potentials (PPs) in CA1 pyramidal neurons that were intrinsically generated by interplay between voltage-gated calcium entry and a Ca(2+)-activated nonselective cation conductance. In the present study, we examined both the second-messenger pathway and the role of synaptic inhibition in the expression of PPs. The stimulation of m1/m3 cholinergic receptor subtypes and G-proteins were critical for activating PPs because selective receptor antagonists (pirenzepine, hexahydro-sila-difenidol hydrochloride, 4-diphenylacetoxy-N-methylpiperidine methiodide) and intracellular guanosine-5'-O-(2-thiodiphosphate) prevented PP generation in carbachol. Intense synaptic stimulation occasionally activated PPs in the presence of oxytremorine M, a cholinergic agonist with preference for m1/m3 receptors. PPs were consistently activated by synaptic stimulation only when oxytremorine M was combined with antagonists at both GABA(A) and GABA(B) receptors. These latter data indicate an important role for synaptic inhibition in preventing PP generation. Both intrinsically generated and synaptically activated PPs could not be elicited following inhibition of serine/threonine protein phosphatases by calyculin A, okadaic acid, or microcystin-L, suggesting that muscarinic-induced dephosphorylation is necessary for PP generation. PP genesis was also inhibited following irreversible thiophosphorylation by intracellular perfusion with ATP-gamma-S. These data indicate that the expression of cholinergic-dependent PPs requires protein phosphatase-induced dephosphorylation via G-protein-linked m1/m3 receptor(s). Moreover, synaptic inhibition via both GABA(A) and GABA(B) receptors normally prevents the synaptic activation of PPs. Understanding the regulation of PPs should provide clues to the role of this regenerative potential in both normal activity and pathophysiological processes such as epilepsy.     

Stage of palate closure as one indication of “liability” to cleft palate

A new inbred mouse strain, SW/Fr, developed from a random-bred SW stock has a 6% incidence of spontaneous cleft palate without cleft lip. SW/Fr mice close their palates comparatively late in development. After cortisone treatment, the mean of the distribution (mean time to reach palate stage 5) is shifted towards later gestational ages. There is no change in the variance of the distribution. These data lend further support to the hypothesis that cleft palate in mice may fit a model where a continuous distribution is separated into discontinuous parts by a developmental threshold, and that time of palate closure is an important component of liability to cleft palate.     

Haemophilus influenzae meningitis. A national study of secondary spread in household contacts.

To determine the risk of severe Haemophilus influenzae illness among household contacts of patients with H. influenzae meningitis, we studied prospective data obtained in 19 states from January 1, 1977, to June 30, 1978. H. influenzae meningitis was reported in 1403 patients, and 1147 (82 per cent) of the exposed families were investigated for the occurrence of H. influenzae disease within 30 days after its onset in the index patient. During this interval, nine of 1687 household contacts (0.5 per cent) under the age of six years had systemic disease confirmed to be caused by H. influenzae Type b. The risk in children less than one year of age was 6 per cent, and the risk in those less than four years of age was 2.1 per cent. None of 2624 contacts above the age of five was affected. In the 30 days after onset of meningitis, the risk of this infection alone, aside from other types of serious H. influenzae disease, is 585 times greater in household contacts than the age-adjusted risk in the general population. The risk of H. influenzae disease in household contacts under six years of age is similar to the risk of secondary meningococcal disease in all household contacts--indicating a need for effective antimicrobial prophylaxis.