Abstract
Building on recent knowledge that the specificity of the biological interactions of small molecule hydrophiles and lipophiles across microvascular and epithelial barriers, and with cells, can be predicted on the basis of their conserved biophysical properties, and the knowledge that biological peptides are cell membrane impermeant, it has been further discussed herein that cellular, and thus, nuclear function, are primarily regulated by small molecule hormone and peptide/factor interactions at the cell membrane (CM) receptors. The means of regulating cellular, and thus, nuclear function, are the various forms of CM Pressuromodulation that exist, which include Direct CM Receptor-Mediated Stabilizing Pressuromodulation, sub-classified as Direct CM Receptor-Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) or Direct CM Receptor-Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) cum External Cationomodulation (≥3+ → 1+); which are with respect to acute CM receptor-stabilizing effects of small biomolecule hormones, growth factors or cytokines, and also include Indirect CM- or CM Receptor-Mediated Pressuromodulation, sub-classified as Indirect 1ary CM-Mediated Shift Pressuromodulation (Perturbomodulation), Indirect 2ary CM Receptor-Mediated Shift Pressuromodulation (Tri or Quad Receptor Internal Pseudo-Cationomodulation: SS 1+), Indirect 3ary CM Receptor-Mediated Shift Pressuromodulation (Single or Dual Receptor Endocytic External Cationomodulation: 2+) or Indirect (Pseudo) 3ary CM Receptor-Mediated Shift Pressuromodulation (Receptor Endocytic Hydroxylocarbonyloetheroylomodulation: 0), which are with respect to sub-acute CM receptor-stabilizing effects of small biomolecules, growth factors or cytokines. As a generalization, all forms of CM pressuromodulation decrease CM and nuclear membrane (NM) compliance (whole cell compliance), due to pressuromodulation of the intracellular microtubule network and increases the exocytosis of pre-synthesized vesicular endogolgi peptides and small molecules as well as nuclear-to-rough endoplasmic reticulum membrane proteins to the CM, with the potential to simultaneously increase the NM-associated chromatin DNA transcription of higher molecular weight protein forms, secretory and CM-destined, mitochondrial and nuclear, including the highest molecular weight nuclear proteins, Ki67 (359 kDa) and Separase (230 kDa), with the latter leading to mitogenesis and cell division; while, in the case of growth factors or cytokines with external cationomodulation capability, CM Receptor External Cationomodulation of CM receptors (≥3+ → 1+) results in cationic extracellular interaction (≥3+) with extracellular matrix heparan sulfates (≥3+ → 1+) concomitant with lamellopodesis and cell migration. It can be surmised that the modulation of cellular, and nuclear, function is mostly a reactive process, governed, primarily, by small molecule hormone and peptide interactions at the cell membrane, with CM receptors and the CM itself. These insights taken together, provide valuable translationally applicable knowledge.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0707-6) contains supplementary material, which is available to authorized users.
Highlights
The specificity of the biological interactions of small molecule hydrophiles and lipophiles can be predicted on the basis of their conserved biophysical properties, which are relative hydrophilicity or lipophilicity in context of molecular size and the distribution of charge over molecular space [1]
In the case of anionic small biomolecule hydrophiles with polyvalent or divalent anionicity such as glutamate, these are impermeant to CM protein channel pores in their polyvalent or divalent anionic forms, closely associate with excess divalent cation, Ca2+, and in association with, auto-endocytose vesiculize into cell membranes [6], as do cationic small biomolecules such as epinephrine and dopamine due to sufficient poly-univalent cationicity in molecular space (2+ cationicity equivalent: 1+ insufficient separation (IS) 1+), while small biomolecules with charge only traverse CM protein channel pores (i.e. Ca2+ channel pores) across looser channel aqueous pores during voltage gating or oxidative stress, as molecular size permits their passage in these specific instances, which is the case of excess Lactate (1−) generated during metabolic acidosis
In the case of the endogenous steriods, these include the corticosteroids and sex steroids, the corticosteroids being small molecules of lipophilic character with van der Waals diameters of ~0.87 nm and the sex steroid hormones being small molecules of lipophilic character with vdWDs of ~0.80 nm, which permeate across inter-epithelial junction pore complexes via diffusion, while both are restricted to permeation across tight junction vascular/microvascular capillary endothelium [1, 7]
Summary
The specificity of the biological interactions of small molecule hydrophiles and lipophiles can be predicted on the basis of their conserved biophysical properties, which are relative hydrophilicity or lipophilicity in context of molecular size and the distribution of charge over molecular space [1].
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