1248

2. Cuneo RC, Salomon F, McGauley GA, Sönksen PH. The growthhormone deficiency syndrome in adults. Clin Endocrinol 1992; 37:387-97.

3. Ziegler TR, Rombeau JL, Young LS, et al. Recombinant human growthhormone enhances the metabolic efficacy of parenteral nutrition: adouble-blind, randomized controlled study. J Clin Endocrinol Metab1992; 74: 865-73.

4. Rudman D. Occasional hypothesis: growth hormone, body composition,and aging. J Am Geriatr Soc 1985; 33: 800-07.

5. Rudman D, Feller AG, Hoskote SN, et al. Effects of growth hormone inmen over 60 years old. N Engl J Med 1990; 323: 1-6.

6. Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR.Continuous subcutaneous infusion of growth hormone (GH) releasinghormone 1-44 for 14 days increase GH and insulin-like growth factor-Ilevels in old men. J Clin Endocrinol Metab 1993; 76: 134-38.

7. Bowers CY, Alster DK, Frentz JM. The growth hormone-releasingactivity of a synthetic hexapeptide in normal men and short staturedchildren after oral administration. J Clin Endocrinol Metab 1992; 74:292-98.

MOLECULAR MEDICINE

Making calcium signals selective

Ten years ago Streb and colleagues reported a second-messenger function for inositol (1,4,5)-trisphosphate(InsP3, which acts through InsP3 receptors to liberate freeintracellular calcium ([Ca2+]) and subsequently to regulatemany cellular processes. [Ca2+] signals can also be

generated by the opening of voltage-gated and receptor-operated calcium channels in the plasma membrane and byactivation of ryanodine-receptor channels. Since multiplehormonal and sensory stimuli may simultaneously use[Ca2+] to effect specific cellular responses, selectivity ofaction must depend on a mechanism for spatiotemporalpatterning of the signal.

Single-cell imaging techniques have revealed a complexpatterning of [Ca2+] propagation in stimulated cells. Cellsstimulated with [Ca2 + ]-mobilising agonists show repetitivepatterns of [Ca2+] spikes, whose frequency is sensitive toboth agonist concentration and the concentration of externalcalcium.2 In addition to this temporal patterning, each spikeoften displays a recurring spatial organisation. There is aspecific initiation locus, from which the calcium spreads as aregenerative wave. For example, the secretagogue-induced[Ca2+] waves in pancreatic acinar cells are initiated in theapical region before propagating towards the basal pole.3[Ca2+] waves propagate through the cytosol using eitherryanodine or InsP3 receptors that are distributed throughthe cytosol on elements of the smooth endoplasmicreticulum and bring about release of intracellular [Ca2+]stores. However, the identity of the messenger responsiblefor wave propagation through the cytosol was, until lately,undefined. Does [Ca+] itself rapidly diffuse to generate thecalcium oscillations or does InsP3 act as the propagatingsignal, initiating localised [Ca2+] release in its diffusionpath? An important step towards understanding themechanisms and dynamics that underlie this process hasbeen reported by workers form the laboratory of Stryer(more familiar to medical students as the author of a populartextbook of biochemistry).

Allbritton et al4 measured the diffusion coefficients andeffective lifetimes of point sources of [Ca2+] and InsP3 andfrom the results determined the physical range of theiraction in the cytosol of Xenopus eggs. Although diffusionconstants for these messengers have previously been

estimated, the values reported in this paper are far moreaccurate and revealing since the researchers have eliminatedinterfering processes such as sequestration, degradation,

and messenger amplification. From their measurements it isclear that after release [Ca2 -’ ], unlike InsP 3’ is rapidly boundto slowly mobile or immobile buffers within the cytosol.Thus, its effective physical range is significantly attenuated.The calculated effective physical ranges of unbuffered[Ca2+], buffered [Ca2+], and InsP3 are 01 1 pm, 5 pm, and24 um, respectively.The rapid buffering of [Ca2 +] makes it an ideal localised

messenger for effector systems that require highconcentrations of for activation. Such effectors mustbe less than 05 pm from a calcium source such as a

voltage-gated calcium channel on the plasma membrane.Once released, the [Ca2+] is rapidly buffered, so that itseffective concentration is profoundly lowered and itsdiffusion slowed. The result is a second domain with a muchlower peak concentration and a range of about 5 jjm.Effectors with high affinity for calcium--eg, thosestimulated by calmodulin--can be activated in this domain.InsP3 seems to have a much larger domain of action becauseit is unbuffered and has a longer effective lifetime. The24 Eun range of InsP3 indicates that it may serve as a globalmessenger, acting across the cytosol of most cells. Takentogether, the evidence suggests that it is InsP3 that acts as thepropagating messenger of the calcium wave, initiating thelocalised release of [Ca2+] from intracellular stores in itswake as it diffuses through the cytosol.The physical and biochemical discrimination of these

signalling domains permits compartmentalisation of thecellular responses. For the clinical investigator, definition ofthe mechanism of compartmentalisation suggests a way toexploit individual signalling domains for therapeutictargeting, thereby offering the opportunity to manipulatedifferent aspects of hormonal and sensory responses. The

subtlety that this approach offers heralds the development ofnovel strategies for fine-tuning physiological and

pathological processes with a balance of functionallyadvantageous and deleterious influences.

Ann Logan

1. Streb H, Irvine RF, Berridge MJ, Schultz I. Release of Ca2+ from anonmitochondrial intracellular store in pancreatic acinar cells byinositol-1,4,5-trisphosphate. Nature 1983; 306: 67-69.

2. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature 1993;361: 315-25.

3. Nathanson MH, Padfield PJ, O’Sullivan AJ, Burgstahler AD, JamiesonJD. Mechanism of Ca2+ wave propagation in pancreatic acinar cells.J Biol Chem 1992; 267: 18118-21.

4. Allbritton NL, Meyer T, Stryer L. Range of messenger action of calciumion and inositol 1,4,5,-trisphosphate. Science 1992; 258: 1812-15.

HYPERTENSION

Exercise for hypertension

Exercise is an effective non-pharmacological way toreduce blood pressure but has received less attention thanother non-drug methods such as weight reduction andrestriction of alcohol or sodium. Moreover, when exercise isrecommended, the details are often vague. A review ofpublished reports in 1984 showed that most studies ofexercise and hypertension were so poorly designed as tomake recommendations difficult.1 However, there is nowreasonable evidence on which to base clinical and publichealth advice.

Various types of exercise have been studied, includingwalking, running, exercising on a cycle ergometer,