Hydrophobicity effect on release and transport of messengers

The cell membrane constitutes a hydrophobic barrier between the cell and its environment. It is constituted of a double layer of lipids (mainly phospholipids but also

Synthesis Phosphatidyl Choline
Figure 14 Synthesis and action of NO*.

glycolipids and cholesterol) wherein proteins are able to 'float'. The membrane lipids (Figure 15) are amphitatic molecules; i.e. they possess a hydrophobic and a hydrophilic part. For the phospholipids, the hydrophobic part is constituted of two long (up to 20 C atoms) hydrocarbon chains. The glycerol moiety, the phosphate group and the attached residue (ethanolamine, inositol, serine and choline) constitute the hydrophilic

Phosphatide acid Phosphatidyl- Phosphatidyl- Phosphatidyls« I ne Phosphatidyl inositol clhanolamine choline

Phosphatide acid Phosphatidyl- Phosphatidyl- Phosphatidyls« I ne Phosphatidyl inositol clhanolamine choline

Phosphatide
Figure 15 Major lipids in membranes of eukaryotic cells. Reprinted from Geoffrey M.Cooper, The Cell: A Molecular Approach, 4th edn., © (2007), with permission from ASM Press, Washington D.C.
Phosphatidyl Choline Structure
Figure 16 Assembly and structure of a phospholipid bilayer.

part. In an aqueous environment lipids tend to aggregate with their hydrophobic regions towards the inside and the polar head groups forming the interface with the water phase (Singer and Nicolson, 1972). Since the lipids have a cylindrical shape, their juxtaposition will result in the formation of a 'flat' lipid bilayer (Figure 16). As a result of its structure, the inner part of the cell membrane will form a hydrophobic barrier (i.e. composed of cholesterol and of the hydrocarbon chains of phospho- and glycolipids) for any compound that would like to enter the cell (Figure 17).

Cell Membrane Hydrophobic Effect
Figure 17 Permeability of the membrane lipid bilayer. Reprinted from Geoffrey M. Cooper, The Cell: A Molecular Approach, 4th edn., © (2007), with permission from ASM Press, Washington D.C.
Table 6 Examples of second messengers which stimulate release of local messengers for effect transmisson.

Structure

Hormone

Neurotransmitter

Local messenger

Small and hydrophobic

Small polar/charged Large polar/charged

Steroids, thyroid hormones, vitamin D, retinoic acid e.g. adrenalin e.g. insulin

e.g. dopamin e.g. enkephalins

NO', eicosanoids e.g. histamine e.g. growth factors

Chemical messengers have varying degrees of hydrophobicity (Table 6). This will profoundly affect their release from the cells in which they are produced, as well as their transport to the receptor.

A limited number of hormones are lipophilic compounds with low-molecular weight: the steroid and thyroid hormones and also retinoic acid and the active metabolite of vitamin D3. Steroid hormones are derived from cholesterol (Figure 18). They are synthetized mainly by endocrine glands such as the gonads (testis and ovary), the adrenals and (during gestation) by the fetoplacental unit.

They all possess the backbone from cholesterol and, at first sight, their structures seem to be pretty much alike. However, they show up to be quite different molecules, when we look at their three-dimensional representation. Accordingly, each steroid hormone can be recognized by a specific receptor. With respect to their biological function, one can distinguish between:

• Female sex steroids: the estrogens (e.g. estradiol) and progestins (e.g. progesteron) are secreted by the ovaries (depending on the stage of the ovarian cycle).

• Male sex steroids: androgens (e.g. testosteron) are produced in the testis and adrenals.

• Corticosteroids (e.g. the mineralocorticoid aldosterone and glucocorticoid cortisol) are produced in the adrenals.

These hormones are hydrophobic enough to freely diffuse across the membrane of the endocrine cells (Figure 19A). Since they cannot be stored in these cells, their secretion can only be modulated by factors which control their synthesis. For example, the transformation of cholesterol into pregnenolon (the first step in the synthesis of all steroid hormones, and occurring in the mitochondria) is under tight external control. Because of their limited solubility in water, hydrophobic hormones are attached to transport proteins (e.g. thyroid binding globulin for thyroid hormones, cortisol-binding globulin for cortisol, etc.) during their journey in the bloodstream. They can diffuse across the plasma membrane of every cell, but only target cells (i.e. those cells that possess the required receptor) will respond. The lifetime of these hormones is also exceptionally long; steroids persist in the blood for hours and thyroid hormones even for days. This

Cholesterol Pregnenolon Testosteron
Figure 18 Synthesis of major steroid hormones by the adrenal cortex. Reprinted from R. Montgomery, T.W. Conway and A.A. Spector, Biochemistry. A Case-Oriented Approach, 5th edn., p. 811. Copyright (1990), with permission from Elsevier.

causes no problem to the organism, since the elicited effects are also long lasting. Receptors for steroids and other hydrophobic hormones are present inside target cells (Figure 19A). A typical target cell for steroid hormones contains about 10 000 receptors. In the absence of hormone, some receptors reside in the cytosol and will move to the nuclear compartment in the presence of the appropriate steroid hormone while others already reside in the nuclear compartment. Interestingly, although eicosanoids (thomboxanes, prostaglandins, leukotrienes) are fatty acid-derived lipids, they interact with receptors that make up part of the plasma membrane (and whose recognition sites are facing the extracellular side of the membrane).

Many local chemical mediators, most hormones and all neurotransmitters are hydrophilic. Their structure is diverse, ranging from small molecules to relatively large

Secreting cell bloodstream Target cell

Secreting cell bloodstream Target cell

Table Hormones Hydrophillic

Secreting cell bloodstream or Target cell ^---synaptic cleft —-—_

external control

Figure 19 A: Secretion, transport and recognition of hydrophobic hormones. B: Secretion, transport and recognition of hydrophilic and peptide messengers.

external control

Figure 19 A: Secretion, transport and recognition of hydrophobic hormones. B: Secretion, transport and recognition of hydrophilic and peptide messengers.

polypeptides (Table 6). Because of their hydrophilicity, these molecules cannot cross any cell membrane. This has profound consequences for their mode of release, their transportation and the subcellular localization of their receptors (Figure 19B). Since these substances cannot diffuse across the membrane from the nerve ending, paracrine or endocrine cell, these hydrophilic molecules can only be released by the process of 'exocytosis'; i.e. by the following steps:

• The chemical messengers are first stored inside small vescicles (possessing a lipid bilayer envelope) in the secretory cell. This enables the secretory cells to build up a reserve of messenger molecules.

• Fusion of the vesicles with the plasma membrane of the secretory cell results in the liberation of the chemical messengers. This exocytotic secretion of messenger molecules is rapid (within milliseconds) and under the control of factors which regulate the fusion of the vescicles with the cell membrane. At the nerve endings (Figure 20), for example, an invading action potential will depolarize the plasma membrane. Voltage-gated calcium channels open, allowing influx of calcium down its concentration gradient. The increased intracellular calcium promotes fusion of transmitter-containing synaptic vesicles with plasma membrane, resulting in exocytosis of vesicular contents. Calcium channels rapidly inactivate and the intracellular calcium is returned to normal by sequestration into mitochondria and active extrusion from the cell.

transmitters

Figure 20 Molecular events involved in neurotransmitter release. A-D represents sequence of events. Reprinted from L.B. Wingard, T.M. Brody, J. larner and A. Schwartz (1991) Human Pharmacology: Molecular to Clinical, p. 234. Copyright (1991), with permission from Elsevier.

transmitters

Figure 20 Molecular events involved in neurotransmitter release. A-D represents sequence of events. Reprinted from L.B. Wingard, T.M. Brody, J. larner and A. Schwartz (1991) Human Pharmacology: Molecular to Clinical, p. 234. Copyright (1991), with permission from Elsevier.

Most of the hydrophilic hormones are removed and/or broken down to inactive metabolites within minutes after entering into the blood, and local chemical mediators and neurotransmitters are removed from the extracellular space even faster: within seconds or milliseconds. Since the hydrophilic messengers cannot cross the cell membrane, the recognition sites of their receptors need face the extracellular side of the plasma membrane. The binding of a messenger molecule constitutes 'information' which these receptors will transfer across the cell membrane, either on their own or in association with other membrane proteins.

Large and/or charged hormones often need to leave the blood vessels to reach their target cells. This means that they cross the capillaries that supply blood to the various tissues. In the periphery, this is possible because there are gaps between the endothelial cells through which the hydrophilic messengers can diffuse to reach other tissues. In the brain, however, the endothelial cells form a continuous wall (Figure 21). Free transfer of hydrophilic messengers between the bloodstream and the brain is therefore rendered impossible (because they need to cross the hydrophobic cell membranes of the endothelial cells). The endothelial cells in the brain thus constitute a barrier, called the 'blood-brain barrier', to circulating messengers. The reason for such a hydrophobic barrier resides in the fact that the extracellular concentrations of hormones, amino acids or ions undergo frequent small fluctuations. To prevent uncontrolled nervous activity, the brain must be kept rigorously isolated from such transient changes in the composition of the blood.

Images Adrenergics
Figure 21 Origin and implications of the blood-brain barrier.
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  • ulrich
    How is hydrophobic messengers transported?
    4 years ago

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